Effectiveness of low-dose erythropoietin in predialysis chronic renal failure patients

Recombinant human erythropoietin (rHuEpo) has been shown tobe both effective and usually safe in patients with chronicrenal failure who have not yet reached the stage requiring dialysis.There are, however, disturbing reports on the possibility ofdeterioration of the reserve renal function in association withrHuEpo therapy. Most of the published studies have used rHuEpoin doses of 50–150 U/kg three times weekly subcutaneously.An open-label trial of rHuEpo therapy was conducted on 21 patientswith chronic renal failure treated sequentially at a referralhospital, rHuEpo was used in doses of 50 U/kg twice weekly for4 weeks followed by 25 U/kg twice weekly for 8 weeks subcutaneously,a regimen substantially lower than current recommendations.This was associated with a gentle but significant increase inhaematocrit (P<0.05) and haemoglobin (P<0.05), while theserum creatinine and the reciprocal of the creatinine remainedstable, with a tendency to improve rather than worsen (P=0.06).We conclude that there is no need to aim at a rapid increasein haematocrit and haemoglobin by rHuEpo therapy; rather a gentleincrease using modest doses is both effective and safe.     

Postoperative intravenous iron used alone or in combination with low-dose erythropoietin is not effective for correction of anemia after cardiac surgery

OBJECTIVES: The aim of this study was to examine whether intravenous iron III-hydroxide sucrose complex (IHSC) used alone was sufficient to provide rapid correction of anemia after cardiac surgery and whether additional stimulation of erythropoiesis is possible by means of a single low dose of recombinant-human erythropoietin (r-HuEPO) administration. DESIGN: Prospective, randomized, double-blind study. SETTING: The study was conducted in a university hospital. PARTICIPANTS: One hundred twenty American Society of Anesthesiologists II or III patients, who underwent elective cardiac surgery using cardiopulmonary bypass and in whom postpump hemoglobin ranged between 7 and 10 g/dL. INTERVENTIONS: Patients were divided into 3 groups: group I = control; group II received postoperative intravenous iron supplementation with an iron III-hydroxide sucrose complex (IHSC); and group III received IV iron and a single dose of r-HuEPO (300 U/kg). MEASUREMENTS AND RESULTS: No significant difference in transfusion needs was observed among the 3 groups (22%, 25%, and 17% of patients transfused in groups I, II, and III, respectively). Hemoglobin levels, reticulocyte counts, and serum ferritin levels were evaluated at different time intervals (until day 30 postoperatively). No side effects because of iron administration were noted in the study. Reticulocyte counts increased rapidly at day 5 (2.24% +/- 1.11%, 1.99% +/- 1.44%, and 3.84% +/- 2.02% in groups I, II, and III, respectively) and decreased after day 15 in the 3 groups. Ferritin levels increased significantly at day 5 in the 2 treated groups (899.33 +/- 321.55 ng/mL in group II, 845.75 +/- 289.96 ng/mL in group III v 463.15 +/- 227.74 ng/mL in group I). In group I, ferritin levels, after a slight elevation on day 5, decreased at day 15 to lower than baseline levels. No significant difference in hemoglobin increase was noted among the 3 groups. CONCLUSION: Postoperative intravenous iron supplementation alone or in combination with a single dose of r-HuEPO (300 U/kg) is not effective in correcting anemia after cardiac surgery.     

Hemodynamic effects of anemia correction by recombinant human erythropoietin in predialysis patients with renal failure

Most patients with chronic renal failure have anemia, which can be corrected by recombinant human erythropoietin (rHuEpo) treatment. Increase in arterial pressure (AP) was reported in some studies and was related to higher systemic vascular resistance induced either by the rise of erythrocyte mass or the change in various endogenous vasopressors, including the direct action of rHuEpo itself. We investigated the effect of rHuEpo treatment on hemodynamic variables, including small and large arterial compliance in 20 patients with chronic renal failure who were not receiving dialysis (CCT 29 +/- 12 mL/min), with Hb levels of 40.4 +/- 0.58 g/dL. They were treated with 2,000 units intravenously followed by 80 to 120 s/c units/kg/body weight, with dosage titration according to Hb level. Noninvasive hemodynamic evaluation was performed before the first rHuEpo treatment, 30 min after the first IV rHuEpo administration and at least 3 months later when target hemoglobin (Hb) and hematocrit (Hct) were reached. No rise in AP occurred after rHuEpo administration either short term or long term. The significant hemodynamic changes were a fall in pulse pressure and a rise in large artery compliance, with no change in small artery compliance after 3 months of rHuEpo treatment when Hb and Hct levels were corrected. These findings show improvement in arterial stiffness when Hb is corrected with rHuEpo treatment.     

Renal function during erythropoietin therapy for anemia in predialysis chronic renal failure patients

Recombinant human erythropoietin (r-HuEPO) therapy for anemia in chronic renal failure patients could have unfavorable renal effects since reversal of anemia can raise blood pressure and accelerate experimental glomerular injury. Thus, the effects of r-HuEPO on renal and systemic hemodynamics and the progression of renal disease were studied in predialysis chronic renal failure patients. The clearances of inulin and p-aminohippurate, fractional excretions of albumin and immunoglobulin G, cardiac output, plasma renin activity and aldosterone concentration were assessed at baseline, after short-term r-HuEPO (n = 4) or placebo (n = 4) therapy, and after long-term r-HuEPO for all patients (n = 8). In addition, the slope of l/serum creatinine with time was determined before and during continued r-HuEPO therapy. In contrast to placebo therapy, hematocrit increased with r-HuEPO from 32 to 37% after 7.6 +/- 2.7 weeks (mean +/- SD). Antihypertensive drug therapy was increased in 2 patients in each group. Renal function, cardiac output, plasma renin activity and aldosterone did not change significantly in either group. After 18 +/- 9 weeks of therapy for all patients, hematocrit increased from 31 to 39%. Antihypertensive drug therapy was increased in 5 patients and decreased in 1. Renal function decreased while proteinuria tended to increase. Cardiac output, plasma renin activity and aldosterone did not change. During 37 +/- 22 weeks of r-HuEPO therapy, the slope of l/serum creatinine did not worsen in any patient.(ABSTRACT TRUNCATED AT 250 WORDS)     

Renal function in predialysis children with chronic renal failure treated with erythropoietin

To assess the effect of long-term administration of human recombinant erythropoietin (EPO) on renal function, 11 anemic children aged 1.4 – 17.2 years were followed for 10 – 61 (mean 31) months on treatment. During EPO therapy the mean hemoglobin rose from 8.1 to 11.1 g/dl at the last observation. The final maintenance dose ranged between 70 and 300 U/kg per week. The rate of deterioration of renal function was calculated by comparing the slope of the regression lines of reciprocal serum creatinine values (SCr) derived from a mean of 20 values per patient obtained over 8 – 50 (mean 29) months before and a mean of 24 SCR values during EPO therapy. The individual slopes improved after initiation of EPO therapy in all but 3 patients, but the mean change of slope (from –0.0521 to –0.0299) was not significant. The study suggests that in most children with predialysis chronic renal failure long-term administration of EPO is not associated with accelerated deterioration but rather with delayed deterioration of renal function. Received August 30, 1995; received in revised form November 16, 1995; accepted April 10, 1996     

Cardiovascular hemodynamic effects of correction of anemia of chronic renal failure with recombinant-human erythropoietin

The results of 8 to 12 weeks of treatment of the anemia of uremia with rHuEPO in patients with chronic renal failure and uremia are: a sustained increased hematocrit; increased RBC mass, and subsequent increased MAP; and increased TPRI. The observed trends of decreased LVEF, and echo Doppler evidence of a trend toward LV systolic and diastolic dysfunction, although not individually statistically significant, represent 3 separate evaluation techniques coupled with hypertension and TPRI increase during administration of rHuEPO to increase the hematocrit and packed red blood cell volume in patients with chronic renal failure and anemia. Increased TPRI and hypertension associated with correction of uremic anemia vasodilation and the increased blood viscosity have been noted in earlier investigations with transfusions. The hypertension and elevated TPRI demonstrated during rHuEPO therapy in patients with progressive chronic renal failure associated with increased hematocrit, and the trends toward systolic and diastolic cardiac dysfunction are noted herein. These changes were associated with the combined increase of packed RBC mass and plasma volume in this study. The natural progressive course of worsening of renal function exhibited by these patients could have limited their ability to regulate plasma volume, making them vulnerable to volume-dependent hypertension and a significant preload adding to potential cardiac dysfunction in addition to the increased TPRI.     

The use of androgens in anaemia resistant to erythropoietin and i.v. iron in patients with heart and renal failure

Sir, We read with interest the recent thorough review of use of androgentherapy in the management of renal anaemia [1]. We have beeninterested in the role of erythropoietin and i.v. iron in the     

Lack of renoprotective effect of i.v. N-acetylcysteine in patients with chronic renal failure

Editor—We read with interest the paper by Ristikankareand colleagues¹ regarding the lack of renoprotective effectof N-acetylcysteine (NAC) in patients with pre-existing renalfailure undergoing cardiac surgery. We feel that several aspectsof this study require further comment. First, a recent meta-analysisof the use of NAC to prevent contrast-induced nephropathy inpatients with renal impairment was inconclusive,² therefore,reducing the evidence base for the rational use of NAC. We wouldalso wish to question the inclusion of patients with plasmacreatinine greater than 100 µmol litre^–1, whichis below the upper limit of     

The effect of correction of anaemia in diabetics and non-diabetics with severe resistant congestive heart failure and chronic renal failure by subcutaneous erythropoietin and intravenous iron.

BACKGROUND: A mild anaemia is often found in patients with congestive heart failure (CHF), but its significance is uncertain. In an open uncontrolled study we investigated the effect of correcting this anaemia [haemoglobin (Hb) 9.5-11.5 g%] with subcutaneous (s.c.) erythropoietin (Epo) and intravenous (i.v.) iron (Fe) in 179 patients, 84 type II diabetics and 95 non-diabetics, with moderate to severe CHF which was resistant to maximally tolerated doses of standard CHF medications. METHODS: Epo, s.c., was given every 1-3 weeks to achieve and maintain the Hb at 12.5 g%. Fe (Fe sucrose-Venofer) was added i.v. as necessary to maintain the Fe stores. Duration of treatment was 11.8 + 8.2 months. RESULTS: With the Epo-Fe treatment the Hb increased from 10.41 +/- 1.0 to 13.1 +/- 1.3 g% in diabetics and from 10.5 +/- 1.0 to 12.9 +/- 1.2 g% in non-diabetics. Comparing the diabetics and non-diabetics, the New York Heart Association functional class improved by 34.8 and 32.4%, respectively. breathlessness and/or fatigue, as measured by a self-administered Visual Analogue Scale, improved by 69.7 and 67.4%, and the left ventricular ejection fraction improved by 7.4 and 11.5%, respectively. The number of hospitalizations fell by 96.4 and 95.3%, respectively, compared with the pre-treatment period. Although the glomerular filtration rate (GFR) was falling at a rate of approximately 1 ml/min/month before the study in both groups, neither the mean serum creatinine nor the GFR changed significantly during the study period. The mean dose of Epo needed, measured in IU/week/kg body weight, was similar in the two groups. CONCLUSION: The correction of the mild anaemia that was found in diabetics and non-diabetics with resistant CHF and mild to moderate chronic renal failure improved the cardiac function and patient functional status, stabilized the renal function and markedly reduced the need for hospitalization.     

Lack of renoprotective effect of i.v. N-acetylcysteine in patients with chronic renal failure undergoing cardiac surgery

Background. Pre-existing chronic renal failure is a significantrisk factor for acute renal failure (ARF) after cardiac surgery.N-acetylcysteine (NAC) has been shown to prevent contrast media-inducedARF. Our objective was to evaluate whether i.v. NAC has renoprotectiveeffects in patients with mild renal failure undergoing cardiacsurgery. Methods. In this prospective, randomized, double-blind study,80 patients with mild to moderate renal failure undergoing electiveheart surgery with cardiopulmonary bypass were recruited. Allreceived either i.v. NAC (n=38) or placebo (n=39) at inductionof anaesthesia and then up to 20 h. Urine N-acetyl-ß-D-glucosaminidase(NAG) and urine creatinine ratio, plasma creatinine, and serumcystatin C levels indicated renal function. Results. Levels of urinary NAG/creatinine ratio, plasma creatinineand serum cystatin C did not significantly differ between NACand placebo groups during five postoperative days. Urine NAG/creatinineratio increased over 30% in 100% of patients in the NAC groupvs 92.3% in the placebo group (P=0.081). Plasma creatinine increasedby 25% from baseline or over 44 µmol litre^–1 in42.1% in NAC group vs 48.7% in placebo group (P=0.560). Serumcystatin C exceeded 1.4 mg litre^–1 in 78.9% in NAC groupvs 61.5% in placebo group (P=0.096). Conclusions. Prophylactic treatment with i.v. N-acetylcysteinehad no renoprotective effect in patients with pre-existing renalfailure undergoing cardiac surgery.     

Total dose infusion iron dextran therapy in predialysis chronic renal failure patients

BACKGROUND: Intravenous iron therapy is now the standard modality of iron supplementation in hemodialysis patients, but its role in predialysis chronic renal failure patients is less well established. The efficacy and safety of intravenous iron dextran as a total dose infusion in predialysis chronic renal failure patients, not receiving erythropoietin was assessed in this study. METHODS: Fifty-six predialysis chronic renal failure patients with anemia, not receiving erythropoietin were included in the study, after obtaining informed consent. Hemoglobin, serum creatinine, creatinine clearance rate and serum ferritin were assessed in all the patients at baseline. Iron dextran in a dose of 1 g dissolved in 500 mL normal saline was administered to all patients as a total dose infusion over 6 h after a prior test dose. Patients were kept in hospital under observation for at least 24 h. All the parameters were repeated in all the patients at 12 weeks and in 21 patients at 1 year. RESULTS: The mean hemoglobin (g/dL) in the patients at baseline and at 12 weeks was 8.28 +/- 0.57 and 9.22 +/- 0.44 respectively (p < 0.001). The mean serum ferritin (ng/mL) increased from 29.73 +/- 9.38 at baseline to 218.43 +/- 15.66 at 12 weeks (p < 0.00001). The mean ferritin value in the 21 patients at 1 year was 136.5 +/- 23.4 (p < 0.01). There were no major adverse events and only minor side effects were observed in 4.9% patients. CONCLUSION: Iron dextran as a total dose infusion corrects anemia in predialysis patients and is an effective method to replenish iron stores. The effect on serum ferritin are evident even at 1 year after the total dose infusion.     

Effect of an educational program on the predialysis period for patients with chronic renal failure

Background The purpose of the treatment and management of chronic renal failure during the predialysis period is mainly to retard the progression of the deterioration of renal function. Optimal dialysis initiation is important to improve the patient's outcome after therapy. We investigated whether providing information through an original educational program could facilitate dialysis initiation, with the patient in a better condition, and therefore greater cost-effectiveness. Methods One hundred and seventy-six patients who underwent dialysis initiation for chronic renal failure in our hospital between April 2002 and March 2005 were divided into two groups according to their participation or nonparticipation in an educational program. Participation in the education program was of their own free will. The instructors consisted of nephrologists, nursing staff, clinical engineering technologists, national registered dietitians, and medical social workers. We investigated whether the education program facilitated trouble-free dialysis initiation by comparing findings of blood tests at the start, the existence of heart-failure symptoms, type of blood access, percentage of scheduled initiation, and the number of days and cost of hospitalization as indices between participating and nonparticipating groups. Results The number of patients using a double-lumen dialysis catheter, and the duration and cost of hospitalization in training the participating group, were significantly less than those in the nonparticipating group. Although there was no significant difference in renal function at the initiation of renal replacement therapy (RRT) between the two groups, serum albumin, hemoglobin, and hematocrit in the participating group were significantly higher than those of the nonparticipating group. Conclusions This study suggests that providing sufficient information before dialysis initiation may be effective in both physical condition at dialysis initiation, and medical economic benefits through the understanding of the dialysis.     

Advanced atherosclerosis in predialysis patients with chronic renal failure

BACKGROUND: Atherosclerosis is advanced in hemodialysis patients as shown by increased intima-media thickness of carotid arteries (CA-IMT), although it is not established whether the advanced atherosclerosis results from hemodialysis treatment or from chronic renal failure. The purpose of this study was to evaluate the effects of hemodialysis and renal failure on CA-IMT in patients with chronic renal failure. METHODS: CA-IMT was measured by high-resolution B-mode ultrasonography in 110 patients with chronic renal failure before starting dialysis (CRF group), and compared with CA-IMT of 345 hemodialysis patients (HD group) and 302 healthy control subjects. They were all nondiabetic and the three groups were comparable in age and gender. RESULTS: As compared with the healthy control subjects, the CRF and HD groups had greater CA-IMTs, whereas CA-IMTs of the CRF and HD groups were not statistically different. There was no significant correlation between duration of hemodialysis and CA-IMT in the HD group. Multiple regression analysis in the total subjects indicated that presence of renal failure, but not being treated with hemodialysis, was a significant factor associated with increased CA-IMT independent of age, gender, blood pressure, smoking, high-density lipoprotein (HDL) and non-HDL cholesterol levels. CONCLUSIONS: These results demonstrate that thickening of arterial wall is present in patients with chronic renal failure before starting hemodialysis treatment, and support the concept that advanced atherosclerosis in hemodialysis patients is due not to hemodialysis treatment, but to renal failure and/or metabolic abnormalities secondary to renal failure.     

The use of recombinant human erythropoietin in the correction of anemia in predialysis patients and its effect on renal function: a double-blind, placebo-controlled trial

Fourteen nondialyzed patients with chronic renal insufficiency (serum creatinine 265 to 972 mumol/L [3.0 to 11.0 mg/dL]) and severe anemia (hematocrit less than 30%) were randomized to receive either recombinant human erythropoietin (r-HuEPO) or a placebo subcutaneously thrice weekly for 12 weeks or until reaching a hematocrit of 38% to 40%. Anemia was significantly ameliorated in the treated patients. No acceleration in the progression of renal failure (1/serum creatinine v time) or change in serum potassium was noted for either the placebo or treated group over the 12-week period. Six of seven treated patients had a significant decrease in serum ferritin and percent transferrin saturation (plasma iron/total iron-binding capacity). This resulted in functional iron deficiency and the requirement for iron supplementation. The average systolic and diastolic blood pressure did not differ significantly between the two groups of patients during the study. Quality of life was improved in all r-HuEPO-treated patients but not in those in the placebo group. This study demonstrates the safety and efficacy of r-HuEPO in the correction of anemia in predialysis patients without adverse effects on renal function over a 12-week period. Improved patient well-being as a result of the correction of anemia resulted in one patient refusing appropriate initiation of dialysis therapy.     

The correction of anemia in severe resistant heart failure with erythropoietin and intravenous iron prevents the progression of both the heart and the renal failure and markedly reduces hospitalization

Both Congestive Heart Failure (CHF) and Chronic Renal Failure (CRF) are increasing steadily in the community. We propose that there is a vicious circle established whereby CHF and CRF both cause anemia and the anemia then worsens both the CHF and CRF causing more anemia and so on. We call this the Cardio Renal Anemia (CRA) syndrome. By the combination of active treatment of the CHF and control of the anemia with subcutaneous erythropoietin and intravenous iron, the progression of both the CHF and the CRF can be slowed or stopped in most cases, the quality of life improved and the need for recurrent hospitalization reduced. This will involve cooperation between internists, cardiologists, and nephrologists to allow early and maximal therapy of both the CHF and the anemia.     

Beneficial influence of recombinant human erythropoietin therapy on the rate of progression of chronic renal failure in predialysis patients.

BACKGROUND: Partial correction of anaemia with recombinant human erythropoietin (rHuEpo) has been shown to markedly improve the general condition and quality of life of predialysis patients, but the effects of rHuEpo therapy on blood pressure and the rate of progression of chronic renal failure (CRF) are still disputed. In particular, no study evaluated the time duration until the start of maintenance dialysis in treated patients, compared to untreated predialysis patients. METHODS: We retrospectively evaluated the rate of decline of creatinine clearance (Delta Ccr) and the duration of the predialysis period in 20 patients with advanced CRF treated with rHuEpo (Epo+ group), and in 43 patients with a similar degree of CRF but with less marked, asymptomatic anaemia, not requiring rHuEpo therapy (Epo- group). All patients were submitted to identical clinical and laboratory surveillance. All received similar oral supplementation with B(6), B(9), and B(12) vitamins and oral iron supplementation. Maintenance dose of subcutaneous epoetin was 54.3+/-16.5 U/kg/week (median dose 3300 U/week). RESULTS: Initial and final haemoglobin (Hb) levels were 8.8+/-0.7 and 11.3+/-0.9 g/dl in the Epo+ group, vs 10.9+/-1.2 and 9.5+/-0.9 g/dl in the Epo- group. In the Epo+ group, Delta Ccr declined from 0.36+/-0.16 during the preceding 24 months to 0.26+/-0.15 ml/min/ 1.73 m(2)/month after the start of rHuEpo therapy (P<0.05). No significant variation was observed in the Epo- group. Time duration until the start of dialysis was 16.2+/-11.9 in the Epo+ group, compared to 10.6+/-6.1 months in the Epo- group (P<0.01). Slowing of progression was observed in 10 Epo+ patients, whereas no significant variation in Delta Ccr occurred in the other 10. There was no difference in previous Delta Ccr rate, nor in Hb or blood pressure levels while on rHuEpo therapy between the two subgroups. CONCLUSIONS: Our study affords conclusive evidence that rHuEpo therapy did not result in accelerated progression of CRF in any treated predialysis patients, nor deleterious increase in blood pressure, but instead resulted in significant slowing of progression and substantial retardation of maintenance dialysis. Such encouraging results remain to be validated in a large prospective, randomized study.