Recombinant erythropoietin improves exercise capacity in anemic hemodialysis patients

The objective of this study was to quantitate the improvement in exercise capacity produced in anemic chronic hemodialysis (HD) patients after correction of their anemia with recombinant human erythropoietin (rHuEPO). The maximal exercise capacity and quadriceps strength of 19 anemic HD patients was tested before and after correction of the anemia with rHuEPO. A progressive work exercise protocol (PWET) on a cycle ergometer was used to compare measurements of maximal oxygen uptake (VO2max), maximal heart rate, and subjective assessment of fatigue during the test. Measurements of quadriceps strength were performed before the cycle ergometer studies. At baseline, all patients had reduced VO2max (15.3 +/- 5.4 mL/kg/min) and maximal exercise heart rates (138.5 +/- 23.9 beats/min). rHuEPO increased the mean hematocrit from 21.2% to 35%, and this was associated with a 17% increase (P less than 0.0005) in the VO2max. At any specified work load, rHuEPO treatment decreased heart rate, minute ventilation, and the subjective perception of fatigue. Both isometric and isokinetic measurements of quadriceps strength were improved following administration of rHuEPO. The maximal exercise heart rate was decreased in comparison to the baseline measurements (P less than 0.04), suggesting that in contrast to normal subjects, HD patients stop exercise before oxygen transport limitations are reached. In this unselected group of chronic HD patients, rHuEPO produced clinically significant improvements in both aerobic exercise capacity and isometric and isokinetic quadriceps strength. The improvement in aerobic capacity was substantially less than would have been expected from the correction of a comparable degree of anemia in non-HD patients. None of the 19 treated patients attained the exercise performance level predicted for a sedentary normal subject.     

Nutritional assessment in anemic hemodialysis patients treated with recombinant human erythropoietin

Nutritional status was assessed in 25 anemic hemodialysis patients before and during erythropoietin treatment. Nutritional assessment included regular blood chemistry determinations, anthropometric measurements, analysis of protein content in skeletal muscle, and estimation of daily protein intake from protein catabolic rate determinations (using urea kinetic modelling) and dialysis efficiency for urea. These measurements were done immediately prior to erythropoietin treatment, after anemia correction and after one year of maintenance erythropoietin treatment. Both relative body weights and subcutaneous fat stores were low at the start, but increased significantly (p less than 0.05) during the study. Sixteen of the 25 patients gained weight and eight patients lost weight. The patients with weight gain had at the start of the study low weight indices (body weight 89.9 +/- 7.6% of ideal body weight, body mass index 20.6 +/- 1.6), significantly (p less than 0.005) lower than the patients with weight loss. Although protein malnutrition was not obvious from arm anthropometrics, alkali soluble protein/DNA ratio or from serum albumin determinations, ASP/DNA ratio, increased in three of five patients investigated after one year on erythropoietin treatment. Neither protein catabolic rate nor dialysis efficiency changed significantly during the study. We conclude that anemia correction with erythropoietin has a positive effect on malnutrition in hemodialysis patients. In patients with underweight, an adjustment of fat stores was initially observed, followed possibly by an improvement in muscle protein content.     

术后镇痛对冠心病患者心肌缺血的影响

目的通过观察冠心病患者术后血浆内皮素（ET-1）、一氧化氮（NO）、6-酮前列腺素F1α（6-Keto-PGF1α）浓度及血压的变化，探讨术后镇痛与心肌缺血的关系。方法胆囊结石合并冠心病患者40例，随机分为A、B两组，硬膜外麻醉复合气管插管全麻，术毕A组接电子镇痛泵，配方为0．125％布比卡因＋芬太尼0．01mg／kg＋格拉司琼3mg，行硬膜外自控镇痛（PCEA）；B组为空白对照组。分别于术前、术毕、术后24h抽静脉血测ET-1、NO、6-Keto-PGF1α血浆浓度。结果A组术后血压平稳，与术前比无明显变化。B组术后24h血压明显升高，收缩压（SBP）、舒张压（DBP）较术前分别升高了16．5％、15．9％。A组和B组ET-1浓度在术后24h较术前均有明显升高，但B组升高更明显（A组为29．2％，B组为77．0％，P〈0．01）；术后24hA组和B组NO浓度较术前分别降低了33．3％和60．0％，6-Keto-PGF1α浓度分别降低了20．3％和42．0％（P〈0．01）。A组术后出现心绞痛及心电图心肌缺血1例，B组6例。结论术后镇痛可减轻手术创伤及术后疼痛引起的舒缩血管物质分泌失衡状态，减少冠心病患者心肌缺血的发生率。     

Human recombinant erythropoietin treatment in transfusion dependent anemic patients on maintenance hemodialysis

Six anemic hemodialysis patients dependent on regular blood transfusions and with massive iron overload were treated with recombinant human erythropoietin (r-huEPO). The effect on absolute reticulocyte count, hemoglobin and serum ferritin was studied during a twenty-week period. Red-cell volume and red-cell life span were measured with 51Cr-tagged erythrocytes at baseline and after twenty weeks of r-huEPO. Absolute reticulocyte counts and hemoglobin concentration rose markedly (from 55.6 +/- 31.2 to a maximum of 174.9 +/- 31.0 x 10(9)/l at 4 weeks and from 6.8 +/- 0.3 to a maximum of 11.2 +/- 1.3 g/dl at 12 weeks, respectively, p less than 0.001) without any further need for transfusions. Red-cell volumes increased concomitantly (from 58 +/- 4 to 81 +/- 11% of normal, p less than 0.005), in spite of a persistent shortening of red-cell life span (45 +/- 18 and 47 +/- 4 days before and after r-huEPO). Markedly elevated serum ferritin concentrations indicating iron overload decreased slowly from 3,550 +/- 1,615 to 2,721 +/- 1,506 micrograms/l (p less than 0.05). It is concluded that r-huEPO is very effective in treating the anemia of patients maintained on hemodialysis. The favorable effects on hemoglobin and red-cell volumes occur in spite of persistent hemolysis and lead to a slow reduction of iron overload.     

Serum malondialdehyde and coronary artery disease in hemodialysis patients

BACKGROUND/AIMS: It has been suggested that enhanced oxidative stress participates in the acceleration of coronary artery disease (CAD) in patients with end-stage renal disease (ESRD). The aim of this study was to investigate the relationship between the level of malondialdehyde (MDA), which is a marker of lipid peroxidation, and the severity of CAD in ESRD patients. METHODS: We conducted a study of 39 hemodialysis patients (median age 58 years; 27 males and 12 females; diabetics 44%). In these patients, the predialysis serum concentrations of MDA and C-reactive protein (CRP) were measured. We performed multirow spiral computed tomography to derive coronary artery calcification (CAC) scores, as a marker of CAD severity. RESULTS: Eleven of the 39 patients had minimal CAC (28%, CAC score <10), 10 patients had mild to moderate CAC (26%, 10-400), and 18 patients had severe CAC (46%, >400). The MDA levels increased (p < 0.05) with increasing CAC category and were correlated (r = 0.35, p < 0.05) with the CAC scores. The levels of MDA also correlated with the serum concentrations of CRP and albumin (r = 0.34, p < 0.05 and r = -0.32, p < 0.05, respectively). Patients in the highest tertile of MDA compared with the other patients were over four times as likely to have severe CAC, and the highest tertile of MDA was an independent predictor of severe CAC, along with a previous cardiovascular event. CONCLUSION: An increased level of MDA, which was associated with inflammatory markers, was a predictive factor for severe CAC in ESRD patients.     

Off-pump coronary artery bypass grafting in patients with end-stage renal disease on hemodialysis

BACKGROUND: Coronary artery bypass grafting (CABG) for hemodialysis patients is high risk compared with other patient groups. The aim of this study was to analyze the potential benefits of off-pump CABG for hemodialysis patients. METHODS: From April 1994 through December 2000, 26 hemodialysis patients underwent CABG. The off-pump group consisted of 15 patients operated on without a pump and the on-pump group consisted of 11 patients operated on with a pump. RESULTS: There was no difference between the two groups with regard to mean age, mean number of diseased vessels and mean number of anastomoses per patient. No patient died in either group during hospitalization. The postoperative complication rate was low in both groups. The postoperative ventilation time was shorter in the off-pump group (8.5 vs 26.1 hours, p < 0.001, respectively [off-pump group vs on-pump group]). The length of ICU stay was shorter in the off-pump group (1.7 vs 3.5 days, p = 0.01, respectively [off-pump group vs on-pump group]). The medial cost was lower in the off-pump group (26,200.80 dollars versus 44,024.10 dollars p = 0.0001 respectively [off-pump group vs on-pump group]). CONCLUSIONS: Off-pump CABG provided excellent less-invasive cardiac surgical results for dialysis patients.     

Influence of fluid removal rate during hemodialysis on left ventricular performance and exercise tolerance in patients with coronary artery disease

The effect of hemodialysis (HD) on left ventricular (LV) function and exercise tolerance were measured at rest and during exercise using gated equilibrium radionuclide ventriculography in seven patients with confirmed coronary artery disease (CAD). To separate the effects of fluid removal rate on LV function in CAD, we investigated the same patients with identical overall volume loss of 4 liters during two different treatment times (4 hr and 2 hr). HD significantly increased resting LV ejection fraction (EF) from 55.7 +/- 8% to 64.7 +/- 8% (P less than 0.01) during the 4 hr HD and from 58.1 +/- 9 to 68.1 +/- 10 (P less than 0.05) during the 2 hr HD. Indicating ischemia, EF decreased at pre- and postdialysis peak exercise without differences between both treatments. HD also resulted in an improved segmental wall motion score. Exercise duration as well as S-T segment depression and angina score improved during HD, whereas heart rate, blood pressure and double product remained unchanged. We conclude that HD improves global and regional resting LV function and exercise tolerance in patients with CAD. The degree of interdialytic hydration and not the degree of fluid removal per time affects LV performance in CAD. Since LV function is the major prognostic factor in CAD, those patients require volume restriction and/or shorter interdialytic phases.     

Comparison of percutaneous coronary intervention with medication in the treatment of coronary artery disease in hemodialysis patients

It has been reported that percutaneous coronary intervention (PCI) is beneficial for coronary artery disease (CAD) among the general population. However, its effects in patients who are on hemodialysis (HD) remain unclear. A prospective cohort study was performed to clarify whether PCI has a therapeutic advantage over medical therapy among HD patients with CAD. A follow-up study to 5 yr was conducted among 259 HD patients with ischemic heart disease. Mean follow-up was 39 mo. Patients were divided into three groups: 122 patients without significant stenosis, 88 patients who had significant stenosis and were treated with PCI, and 49 patients who had significant stenosis and were treated with medication only. The primary end point was cardiac death, and the secondary end point was all-cause death. The results showed that the 5-yr cardiac survival rate was 41.6% in the medication group, 77.1% in the PCI group (P = 0.0006), and 84.5% in the nonstenosis group (P < 0.0001). The 5-yr all-cause survival rate was 19.3% in the medication group, 48.4% in the PCI group (P = 0.004), and 64.3% in the nonstenosis group (P < 0.0001). Even after adjustment for other risk factors, effects of PCI on the risk for cardiac and all-cause death remained significant and independent (odds ratio 0.14; 95% confidence interval 0.08 to 0.25, P = 0.0006; and odds ratio 0.37; 95% confidence interval 0.26 to 0.54, P = 0.0062, respectively). Results were consistent when the therapeutic effect of PCI or medication was analyzed using propensity-matched patients. These data suggested that PCI could improve the prognosis of HD patients with CAD. PCI would be recommended for HD patients with CAD.     

Prognostic value of nonlinear heart rate dynamics in hemodialysis patients with coronary artery disease

BACKGROUND: Although altered nonlinear heart rate dynamics predicts death in patients with coronary artery disease (CAD), its prognostic value in chronic hemodialysis patients with CAD is unknown. METHODS: We analyzed 24-hour electrocardiogram for nonlinear heart rate dynamics and heart rate variability in a retrospective cohort of 81 chronic hemodialysis patients with CAD. RESULTS: During a follow-up period of 31 +/- 20 months, 19 cardiac and 8 noncardiac deaths were observed. Cox hazards model, including diabetes, left ventricular ejection fraction, and the number of diseased coronary arteries, revealed that abnormal alpha2 (defined as both increase and decrease in alpha2 because of its J curve relationship with cardiac mortality), decreased approximate entropy and decreased heart rate variability (triangular index and ultra-low frequency power) were significant and independent predictors of cardiac death. No significant and independent predictive power for noncardiac death was observed in either the heart rate dynamics or the heart rate variability measures. The predictive power of alpha2 and approximate entropy was independent of that of triangular index and ultra-low frequency power. Combinations of two categories of measures improved the predictive accuracy; overall accuracy of approximate entropy + ultra-low frequency power for cardiac death was 87%. CONCLUSION: Altered nonlinear heart rate dynamics are independent predictors of cardiac death in chronic hemodialysis patients with CAD and their combinations with decreased heart rate variability provide clinically useful markers for risk stratification.     

Wartime determinants of arteriographically confirmed coronary artery disease in Beirut

This study investigates the association of wartime stress variables and coronary artery disease as determined by coronary angiography in Lebanon in 1986, a country with an ongoing civil war for ever a decade. A total of 127 patients who underwent coronary angiography at the American University of Beirut Medical Center were individually matched on age and sex with visitor controls free from any evidence of clinical coronary artery disease. Arteriographic cases (greater than or equal to 70% maximal stenosis) were compared with two control groups: arteriographic controls (entirely normal coronaries) and visitor controls. Findings suggest that there is a relation between exposure to both acute and chronic war events and coronary artery disease in this patient population. The reporting of exposure to acute war events was significantly higher in cases compared with both visitor controls (odds ratio (OR) = 2.4, 95% confidence interval (CI) 1.17-4.90) and arteriographic controls (OR = 2.8, 95% CI 0.93-8.47). Crossing the "green-lines" that separate two belligerent sides, considered as an attribute of war-related chronic stress, was more frequent in cases compared with visitor controls (OR = 3.25, 95% CI 1.54-6.89) and arteriographic controls (OR = 5.38, 95% CI 1.65-17.6). The relation observed between wartime stress and coronary artery disease could not be explained by possible overreporting of stressful events in patients with suspected coronary artery disease or by an increase in clinical awareness for the disease for those under continuous stress. Adjusting for the effect of the well-established coronary artery disease risk factors did not alter the above findings.     

静脉补铁对肾性贫血促红细胞生成素的治疗效果

目的比较静脉补铁与口服补铁对慢性肾脏疾病患者使用促红细胞生成素（EPO）治疗贫血的效果。方法选择58例初次使用铁剂及EPO治疗慢性肾功不全的透析患者。试验前检查每位患者的血红蛋白（Hb）、红细胞比容（Hct）、血清铁（SI）、血清铁蛋白（SF）、总铁结合力（TIBC）、转铁蛋白饱和度（TSAT）。Hct〈33％作为贫血指标。将患者随机分为静脉补铁组（30例）和口服补铁组（28例）,静脉补铁组予以低分子右旋糖酐氢氧化铁复合物注射液（科莫非）100mg,每周2次;口服组予以右旋糖酐铁225mg／d。两组均予以EPO10000单位／周,皮下注射。4周后复查上述指标。结果试验结束时,静脉补铁组各项铁参数指标明显高于口服补铁组;静脉补铁组贫血改善较口服服补铁组好,两组Hb和Hct上升有明显差异。结论在使用EPO的同时,静脉补铁较口服补铁能更快、更好地改善肾性贫血。     

Effect of erythropoietin on cardiovascular prognosis parameters in hemodialysis patients

BACKGROUND: Renal anemia is an important determinant for left ventricular hypertrophy in dialysis patients and an independent prognosis parameter for the cardiovascular survival in dialysis patients. In addition, an autonomic dysfunction is associated with the uremic state and influences the cardiovascular risk in patients with end-stage renal disease (ESRD). METHODS: We investigated in this prospective longitudinal study the effect of hemoglobin normalization by a chronic treatment with recombinant human erythropoietin (rhEPO) on cardiovascular prognosis parameters in 23 patients on chronic hemodialysis with renal anemia (hemoglobin concentration < or =10.5 g/dL) and echocardiographically proven left ventricular hypertrophy. We studied muscle sympathetic nerve activity measured by microneurography; cardiopulmonary baroreflex activity by lower-body negative pressure (LBNP-) testing; left ventricular structure and mass index (LVMI) by echocardiography; blood pressure by 24-hour readings; peripheral blood flow and vascular resistance by plethysmography before (U1) and after 7 months of chronic rhEPO treatment (U2). RESULTS: In the anemic state, mean (+/- SD) muscle sympathetic nerve activity in ESRD was elevated (U1 rest, 34 +/- 13 bursts per minute) and cardiopulmonary baroreflex response during LBNP markedly lacking (U1 -15 mm Hg, 34 +/- 13 bursts per minute) reflecting a severely impaired autonomic function. Normalization of the hemoglobin concentration by chronic rhEPO treatment (U1, 10.5 +/- 0.9 g/dL versus U2, 13.4 +/- 3.1 g/dL, P <0.001) did not influence sympathetic nerve activity (U2, 34 +/- 15 bursts per minute, NS) and cardiopulmonary baroreflex sensitivity did not change (U2 -15 mm Hg, 37 +/- 16 bursts per minute, NS). LVMI decreased significantly after chronic treatment with rhEPO (U1, 134 +/- 26 g/m2 versus U2, 97 +/- 25 g/m2, P < 0.001) and left ventricular geometry developed from an asymmetric to a symmetric configuration (U1, relative wall thickness 0.58 versus U2, 0.43, P < 0.001). Under treatment with rhEPO, 24-hour systolic and diastolic blood pressure did not increase (systolic U1, 132 +/- 4 mm Hg versus U2, 128 +/- 3 mm Hg, NS, and diastolic U1, 76 +/- 2 mm Hg versus U2, 73 +/- 2 mm Hg, NS). Peripheral blood flow (U1, 6.1 +/- 3.3 mL/100 mL/min versus U2, 6.2 +/- 0.6 mL/100 mL/min, NS) as well as forearm vascular resistance (U1, 15.7 +/- 3.3 mm Hg/mL/100 mL versus U2, 14.9 +/- 3.1 mm Hg/mL/100 mL, NS) did not change by chronic rhEPO treatment. CONCLUSION: Normalization of hemoglobin by chronic rhEPO treatment in dialysis patients has beneficial cardiovascular effects with regression of left ventricular hypertrophy and improvement of left ventricular geometry. However, a reduction of sympathetic overactivity or a resetting of baroreceptor sensitivity by a rhEPO treatment in dialysis patients in the medium-term could not be demonstrated. The reason for this may be the complex and multifactorial pathomechanism of autonomic dysfunction and cardiovascular disease in ESRD.     

The value of computed tomography-derived coronary artery calcification score in coronary artery disease detection in asymptomatic hemodialysis patients

BACKGROUND: We evaluated the value of coronary artery calcification (CAC) score in coronary artery disease (CAD) detection in asymptomatic hemodialysis (HD) patients by evaluating the association among CAC score, exercise electrocardiography (EECG), and Thallium-201 dipyridamole scintigraphy. Correlation between aortic pulse wave velocity (PWV) and CAC score was also evaluated. METHODS: CAC score was assessed with conventional computed tomography in 40 patients. Thirty patients completed EECG and 25; those with a positive CAC score and/or a positive EECG performed Thallium dipyridamole scintigraphy. Carotid-femoral PWV was assessed in all patients. RESULTS: There was no association among CAC score and EECG or Thallium dipyridamole scintigraphy. In contrast, CAC score was correlated with aortic PWV. CONCLUSION: The previous results question the role of CAC score in the detection of CAD in asymptomatic HD patients. The correlation between CAC score and aortic PWV raises the possibility that CAC score represents more an indicator of coronary artery medial wall calcification than a marker of CAD.     

Autologous blood donation with recombinant human erythropoietin in anemic patients

BACKGROUND: Various blood management strategies can be used to reduce the need for allogeneic blood in cardiac surgery. In anemic patients, however, avoidance of allogeneic blood transfusion is difficult to achieve. This study was performed to assess the safety and effectiveness of preoperative blood collection using recombinant human erythropoietin (rHuEPO) for reducing the exposure to allogeneic blood in anemic patients. METHODS: Thirty-two anemic patients undergoing cardiac surgery at our hospital between January 1994 and October 1997 were divided into two groups according to preoperative strategies: 3-week treatment with rHuEPO and blood donation (group 1, n = 16) or iron supplementation alone (group 2, n = 16). RESULTS: There were no statistically significant differences between the two groups in patients' characteristics and surgical data. The number of reticulocytes was increased at just before surgery in group 1, whereas group 2 showed no significant increase. The estimated hemoglobin increases in group 1 were higher at 7 days and just before surgery. The mean number of required allogeneic blood for patients during surgery was 0.59 +/- 1.12 U in group 1 and 5.01 +/- 2.63 U in group 2. In 75% of group 1 patients, allogeneic blood transfusion was successfully avoided, whereas all patients in group 2 received allogeneic blood. CONCLUSIONS: This study suggests that the combination of rHuEPO administration and autologous blood donation can reduce the need for allogeneic blood in anemic patients.     

Clinical significance of natriuretic peptides and cyclic GMP in hemodialysis patients with coronary artery disease

BACKGROUND: Plasma concentrations of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and cyclic guanosine monophosphate (cGMP) are suitable markers of 'dry body weight' (DW) in hemodialysis (HD) patients. However, it is still unknown whether these markers can be applied to patients with renal failure and coronary artery disease (CAD). We examined the reliability of these peptides as volume markers in HD patients with CAD. We also assessed the relationship between natriuretic peptides and indices of left ventricular (LV) function. METHODS: Plasma concentrations of ANP, BNP and cGMP were determined before and after HD in patients with CAD (group 1, n = 19, mean age 63 +/- 12 years) and were compared with those of patients without cardiac disease (group 2, n = 20, age 61 +/- 15 years). Using data obtained by cardiac catheterization, we examined the relationship between natriuretic peptides and indices of LV function in HD patients with CAD. RESULTS: Baseline ANP (244 +/- 205 pg/ml), BNP (713 +/- 928 pg/ml) and cGMP (29.6 +/- 21.6 pmol/ml) were significantly higher in group 1 than in 11 healthy volunteers (18.6 +/- 9.9 pg/ml, 7.7 +/- 7.6 pg/ml, cGMP 8.9 +/- 4.9 pmol/ml, respectively). HD significantly reduced plasma ANP (87 +/- 75 pg/ml) and BNP (477 +/- 702 pg/ml) although they were still above normal control. HD reduced plasma cGMP (7.2 +/- 4.5 pmol/ml) to normal values, suggesting the elimination of cGMP across the dialyzers. Baseline levels of ANP, BNP and cGMP in group 2 were less than those of group 1 but higher than the control. HD reduced natriuretic peptides in group 2 to levels lower than those in post-HD group 1. After HD, there was no significant correlation between reductions in body weight and changes in ANP or BNP. Baseline ANP and BNP levels closely correlated with pulmonary artery pressure, pulmonary artery wedge pressure, left ventricular end-diastolic pressure and left ventricular ejection fraction. A significant correlation was observed between BNP levels and the severity of CAD. CONCLUSION: ANP, BNP and cGMP seem to be a useful markers for fluid overload but not for DW in HD patients with CAD. Plasma ANP and BNP might be useful markers for left ventricular function.