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.     

Efficacy prospective study of different frequencies of Epo administration by i.v. and s.c. routes in renal replacement therapy patients.

BACKGROUND: The problem of pure red cell aplasia (PRCA) prompted nephrologists to revert to a wider intravenous (i.v.) utilization of erythropoeitin (Epo). Once weekly i.v. Epo administration has been suggested to be as effective as the twice/thrice weekly i.v. dose. The aim of the present study was to test whether once weekly i.v. Epo administration is equally as cost-effective as once weekly subcutaneous (s.c.) and 2-3 times weekly i.v. administration. METHODS: We prospectively studied 41 patients (23 males, aged 28-82 years), on renal replacement therapy for 18-286 months, stabilized on twice or thrice weekly s.c. Epo-alpha (basal). The patients were treated for three consecutive 6 month periods with once weekly s.c. (OWSC), once weekly i.v. (OWIV) and twice/thrice weekly i.v. (TWIV) Epo-alpha. The initial dose for each period was equal to the final dose of the previous one; when necessary, the dose was adjusted according to DOQY guidelines. Iron, folic acid and vitamin B(12) supplementations were given throughout all the study periods. At the end of each of the four study periods, the following parameters were evaluated: haemoglobin, haematocrit, hypochromic red blood cells (RBCs), iron, serum ferritin, transferrin, folate, vitamin B(12), C-reactive protein (CRP), Kt/V, parathyroid hormone (PTH) and weekly dose of Epo-alpha. RESULTS: Thirty-three out of 41 enrolled patients completed the study (there were five deaths, two renal transplants and one transfer). No significant changes were observed as regards iron, serum ferritin, transferrin, folate, vitamin B(12), CRP, Kt/V or PTH level. Haemoglobin levels were not different at the end of the basal (11.7+/-1.21), OWSC (11.8+/-0.86) and TWIV (12.1+/-1.04) periods, while significantly lower levels were observed after the OWIV period (11.0+/-0.97, P<0.01). Weekly Epo consumption (Epo U/week/kg body weight/g haemoglobin) was: basal 11.57+/-5.96; OWSC 10.22+/-4.53; OWIV 15.99+/-7.7*(a); and TWIV 11.89+/-6.3*(a) (*P<0.01 vs basal; (a)P<0.01 vs OWSC). CONCLUSIONS: From our results, the OWIV schedule seems to have less efficacy in the control of anaemia of chronic renal failure patients on dialysis treatment than either OWSC or TWIV schedules.     

Effect of recombinant human erythropoietin on erythropoiesis in homozygous sickle-cell anaemia and renal failure.

The development of end-stage renal disease (ESRD) in patients with sickle-cell anaemia results in increased transfusion dependence, increasing the risk of iron overload. Correction of anaemia with recombinant human erythropoietin (rHuEpo) in dialysis patients might also result in stimulation of haemoglobin F production, which protects against sickling, although very high doses were required to achieve this effect in non-uraemic animals. rHuEpo was administered to three transfusion-dependent patients with ESRD and homozygous sickle-cell disease (initial dose 100 U/kg twice weekly, increasing to 125 U/kg at 6 weeks, and to 150 U/kg at 9 weeks in two patients). This resulted in reticulocytosis and increased circulating erythroid blast-forming units. Total haemoglobin was predominantly HbA (i.e. transfused blood) at the start of the study, reflecting transfusion dependence, but after 3 months' treatment was between 60 and 94% HbS. No sickling crises occurred. Haemoglobin F remained at less than 3% of total haemoglobin. One patient was withdrawn at 10 weeks with CAPD peritonitis. The other two patients completed 12 weeks' treatment without transfusion but final Hb concentrations were 4.5 and 5.5 g/dl. Whether larger doses of rHuEpo will be more successful in managing such patients remains unclear. No effect on HbF production can be expected.     

A prospective multicentre study of the role of anaemia as a risk factor in haemodialysis patients: the MAR Study.

BACKGROUND: Retrospective studies have shown hospitalization and mortality rates during haemodialysis (HD) to be associated with anaemia. METHODS: The prospective, multicentre Morbidity-and-mortality Anaemia Renal (MAR) study was designed to establish the burden of anaemia by controlling for other risk factors. Charlson index was used for comorbid adjustment. Finally, 1428 patients from 119 centres (60% men, aged 64.4 years, time on HD 15.3 months, Charlson comorbidity index 6.5 +/- 2.3) completed follow-up. They had hypertension (75.8%), diabetes mellitus (25.9%), heart failure (13.9%) and coronary disease (16.7%). Of the total patients, 94.8% were receiving erythropoietin (111.6 +/- 70.6 U/kg/week) and 76.7% i.v. iron, and haemoglobin (Hb) at inclusion was 11.7 +/- 1.5 g/dl. RESULTS: Hospitalization rate was 1.1 admissions/patient/year. Yearly mortality was 12% [35% cardiovascular (CV)]. The relative risk and confidence interval (CI) for hospitalization and death were 0.86 (0.81-0.91) and 0.82 (0.73-0.91), respectively, per 1 g/dl increase in initial Hb after adjustment for comorbidity, vintage, aetiology, access type, albumin and Kt/V. The probability of remaining free from hospitalization (CI) was 0.34 (0.27-0.41) for initial Hb <10 g/dl, 0.47 (0.41-0.53) for Hb 10-11 g/dl, 0.54 (0.49-0.59) for Hb 11-12 g/dl, and 0.63 (0.59-0.67) for Hb >12 g/dl. Same analysis for patient survival was 0.77 (0.71-0.83) for Hb <10 g/dl vs 0.82 (0.77-0.87) for Hb 10-11 vs 0.89 (0.86-0.92) for Hb 11-12 vs 0.92 (0.90-0.94) for Hb > 12 g/dl, P < 0.001. The Cox regression model for hospitalization-free survival included the risk factors initial Hb (relative risk 0.86 per 1 g/dl increase, P < 0.001) Charlson, albumin and prior CV event. CONCLUSION: Hb level predicted 1-year-survival and hospitalization. This effect persisted after adjustment for comorbidity and other prognostic factors.     

Level of renal function and serum erythropoietin levels independently predict anaemia post-renal transplantation.

BACKGROUND: Post-renal transplant anaemia is a potentially reversible cardiovascular risk factor. Graft function, immunosuppressive agents and inhibition of the renin-angiotensin system have been implicated in its aetiology. The evaluation of erythropoietin (EPO) levels may contribute to understanding the relative contributions of these factors. METHODS: Two-hundred and seven renal transplant recipients attending the Belfast City Hospital were studied. Clinical and laboratory data were extracted from the medical records and laboratory systems. RESULTS: Of the 207 patients (126 male), 47 (22.7%) were found to be anaemic (males, haemoglobin (Hb)<12 g/dl, females Hb<11 g/dl). The anaemic group had a significantly higher mean serum creatinine level (162.8 micromol/l vs 131.0 micromol/l, P<0.001) and lower mean estimated glomerular filtration rate (eGFR) (41.5 ml/min vs 54.9 ml/min, P<0.001) than the non-anaemic group. Individual immunosuppressive regimens were comparable between those with and those without anaemia. Angiotensin converting enzyme inhibitor (ACE-I) or angiotensin receptor blocker (ARB) administration was not more prevalent in those with anaemia compared with those without (36.2 vs 38.8%, P=0.88). There was a significant inverse correlation between Hb levels and serum EPO levels (R=-0.29, P<0.001), but not between EPO levels and eGFR (R=0.02, P=0.74). Higher EPO levels were predictive of anaemia, independent of eGFR in multivariate analysis. CONCLUSION: Anaemia is common in post-renal transplant patients. The levels of renal function and serum EPO and not immunosuppressive regimens or ACE-I/ARB use, are strong and independent predictors of anaemia.     

Haemodynamic changes and exercise tolerance in dialysis patients treated with erythropoietin

The aim of our study was to evaluate cardiovascular functionat rest and during exercise in dialysis patients before andafter treatment with Epo and to examine the changes in leftventricular mass as the consequence of treatment for anaemia.We applied echocardiography and radionuclide ventriculographyat rest and after exercise in our research. Following treatmentwith Epo there was a decrease in the initially high cardiacoutput (CO) and cardiac index (CI) from 7.5 to 6.3 1/min andfrom 4.3 to 3.6 1/min/m² respectively. No changes were notedin mean diastolic (DPB) and mean blood pressure (MBP), as wellas the initially increased peripheral resistance index (TPRi)of 2582.3 ± 2097.3 dyn-s-cm^–5 m². Nevertheless,end-diastolic (EDV) and endsystolic (ESV) volume were significantlydecreased (P < 0.05), but the ejection fraction (EF) remainedunchanged (73.9%). The decrease in the mean values for leftventricular mass (LVM) was significant only within the subgroupof dialysed patients who initially had larger left ventricularmass (P < 0.01). The functional capacity of the CV systemmeasured during exercise increased from four metabolic equivalents(METs) to 6 METs (P < 0.01). A significant increase in bloodvolume was also observed following treatment of anaemia. The haemodynamic consequences of Epo therapy for the treatmentof anaemia were quite positive. However, we would like to pointout certain concerns regarding the dialysed patients with initiallylower values for left ventricular mass and cardiac output, sincethe patients within this group developed left ventricular hypertrophyand an increase in cardiac output.     

Long-term effects on quality of life in haemodialysis patients of correction of anaemia with erythropoietin

Quality of life assessments were performed in 24 haemodialysispatients (10 males, 14 females, age 45 ±15 years) undergoingrHuEpo treatment. The results in the rHuEpo-treated patientswere compared with those in eight haemodialysis patients noton rHuEpo and with the results of a nationwide study of dialysispatients in Sweden (carried out before rHuEpo was registered).Survey questionnaires (112 items, divided into three dimensions,i.e. physical, social, and emotional wellbeing) were completedbefore treatment (Hb 73± 1.1 g/1), when the target Hbvalue of 10 g/dl was reached (1–7 months) and in 14 patients1 year after correction of the anaemia. Before treatment, therHuEpo group had significantly more complaints about poor appetite,fatigue, and irritability than the controls. After the anaemiawas corrected, the rHuEpo group had significantly improved physicaland emotional wellbeing. The most significant changes occurredin satisfaction with health, physical activities of daily life,and fatigue. Alterations in emotional symptoms, such as depressionand apathy, were less pronounced. Only minor changes were observedin their social wellbeing. One year after correction of theanaemia, the improvements in physical and emotional wellbeingwere still present in the rHuEpo-treated patients. A positiveeffect was also noted on hospitalization rate. Scores for thesubdimensions of satisfaction with health, sexual adjustment,physical symptoms, and emotional wellbeing improved in the rHuEpo-treatedgroup and reached a level that was the same, or even higher,than the scores in the dialysis patients in the nationwide study.In conclusion, the quality of life improved during rHuEpo treatment.The greatest changes were seen in satisfaction with health,physical activity, and emotional wellbeing. The positive effectsobserved after the correction of anaemia persisted after morethan a year on rHuEpo treatment.     

Heart and iron deficiency anaemia in rats with renal insufficiency: the role of hepcidin

Aim: Anaemia is prevalent in chronic kidney disease (CKD) and induces significant changes in heart and kidney. In this study, we evaluated the relationship between iron metabolism, hepcidin and inflammation focusing on left ventricular (LV) function, in a remnant kidney rat model. Methods: Rats with 5/6 subtotal nephrectomy (STNx) and sham operation. Haemoglobin (Hb), serum iron (SI), fractional shortening (FS%) by echocardiograms were evaluated. Six months after STNx, the heart and kidney were processed by immunohistochemistry with antibodies against hypoxia-inducible factors (HIF)-1α, erythropoietin (EPO), pro-hepcidin, caspase-3, tumour necrosis factor (TNF)-α and interleukin (IL)-6. Results: Hb (g/dL) STNx: 10.8 ± 0.8, sham: 14.7 ± 0.6 (P < 0.01); SI (µg/dL) STNx: 154.5 ± 24.5, sham: 287.5 ± 32.1 (P < 0.01); heart weight (g) STNx: 2.21 ± 0.15, sham: 1.12 ± 0.12 (P < 0.01); FS% STNx: 28.4 ± 2.5, sham: 45.1 ± 4.1 (P < 0.01). There was a correlation between Hb and FS% (r = 0.95; P < 0.01) and between SI and FS% (r = 0.86; P < 0.01) in the STNx group. Tissue ferritin was reduced in heart and in kidney in the STNx group (P < 0.01). HIF-1α was expressed in cardiomyocytes (positive cells/area) STNx: 32 ± 5, sham: 4 ± 1; and tubular cells in STNx group: 70 ± 16, sham: 10 ± 3, P < 0.01. Hepcidin (% staining/area) in heart STNx: 6.6 ± 0.8, sham: 0.8 ± 0.1; in kidney STNx: 9.7 ± 2.6, sham: 3.7 ± 0.9, P < 0.01. EPO (% staining/area) in heart STNx: 2.6 ± 0.4, sham: 0.8 ± 0.2; in kidney STNx: 10.2 ± 1.4, sham: 1.2 ± 0.6; P < 0.01. In STNx group positive caspase-3, TNF-α and IL-6 were detected in heart and renal cells. Conclusion: Low LV performance is associated with iron deficiency anaemia in rats with CKD. Furthermore, overproduction of HIF-1α and the activation of caspase-3 seem to be associated with iron deficiency and with inflammatory markers. Hepcidin seems to plays a key role in this mechanism.     

Recombinant human erythropoietin corrects anaemia during the first weeks after renal transplantation: a randomized prospective study

BACKGROUND.: Studies on the effect of recombinant human erythropoietin (rHuEpo)on haematopoiesis in patients with kidney transplants, havebeen limited to progressive chronic graft failure, late aftertransplantation. In the present prospective randomized study,the efficacy of rHuEpo in the correction of anaemia during thefirst weeks after renal transplantation (RTP) was evaluated. METHODS.: Patients were allocated to either an Epo-(n=14) or a non-Epo-treatedgroup (n=15). Epo (150 U/kg.week s.c.) was started at a haematocrit(Hct) <30% and was increased at weekly intervals by 30 U/kg.week,as long as Hct remained <25%. RESULTS.: In the Epo group, Hct increased from a nadir of 22±4%2 weeks after RTP to 30±4% at week 4 and to 36±4%at week 6 (P<0.001 and P<0.0001 respectively vs week 2).Corresponding values in the non-Epo group were 25±6%,28±6% (P=NS) and 32±6% (P<0.05 vs week 2) (overallevolution Epo vs non-Epo: P=0.038 by variance analysis). Thedifferences in Hct between the Epo and non Epo group were evenmore marked in patients without major complications (varianceanalysis P=0.009). The Epotreated patients required fewer post-surgicalblood transfusions (0.005 vs 0.014/days follow-up, P<0.05),in spite of greater post-surgical blood losses, especially atday 1 (P<0.05) and the presence of more major complications(7 vs 4) and a higher number of ganciclo vir-treated patients(4 vs 0; P<0.05). The maximum Epo dose after RTP was >2xhigher than the one required before RTP (197.1±45.1 vs85.0±76.0 U/kg.week; P<0.05). CONCLUSIONS.: It is concluded that rHuEpo during the first weeks after RTPis of benefit in the correction of the Hct in the early post-surgicalperiod, in spite of relative Epo resistance.     

Low-dose subcutaneous erythropoietin corrects the anaemia of renal transplant failure.

Although erythropoietin (Epo) is known to correct anaemia in dialysis and pre-dialysis patients, there is limited experience with its use in immunosuppressed patients suffering from chronic renal graft dysfunction. We report the results of a pilot study of Epo in seven patients with failing grafts and normocytic normochromic anaemia attributable to renal failure. All entering patients had controlled blood pressure and serum ferritin greater than 100 micrograms/l. Three patients were taking triple immunotherapy (prednisone/azathioprine/cyclosporin), two patients prednisone/azathioprine, and two patients CsA monotherapy. Study duration mean was 15 +/- 2 (SEM) weeks, and Epo was started at 4000 units subcutaneously (s.c.) once weekly, adjusted to achieve a target haemoglobin (Hb) of 100 g/l. Mean Hb at initiation was 68 +/- 5 g/l and significantly increased to 96 +/- 6 at end of follow-up, P less than 10(-4). All patients responded. Maintenance Epo dosage was 120 +/- 32 U/kg bodyweight/week, roughly 4000 units/week. There was no significant change in serum creatinine: pre-study 392 +/- 45 mumol/l; post-study 430 +/- 62 mumol/l. There were no complications but blood pressure did rise significantly: pre- 124 +/- 11/74 +/- 4 mmHg to post- 142 +/- 10/86 +/- 3, P less than 0.05 for systolic and diastolic. Low-dose s.c. Epo effectively corrects anaemia in graft failure despite azathioprine and/or CsA therapy, without obvious acceleration of graft failure.(ABSTRACT TRUNCATED AT 250 WORDS)     

Serum erythropoietin concentrations and responses to anaemia in patients with or without chronic kidney disease.

BACKGROUND: Renal anaemia is caused by a relative erythropoietin (EPO) deficiency. Due to difficult interpretation of serum EPO concentrations adapted to anaemia and renal function, the diagnostic value of measuring serum EPO concentrations is limited. METHODS: We retrospectively analysed the relationship between haemoglobin and serum EPO concentrations routinely measured in in- and out-patients of our university hospital from 2001-04. Patients under EPO substitution or those with acute renal failure, polycystic kidney disease, renal carcinoma or polycythaemia due to pulmonary disease were excluded. The study population (n = 500) was then stratified according to the presence or absence of chronic kidney disease (CKD) and to the stage if CKD was present. EPO concentrations were expressed in percentiles corrected for the severity of anaemia and based on the EPO response in patients without CKD. RESULTS: In patients without CKD (n = 167) there was a strong parametric correlation between severity of anaemia and increase in EPO (r = -0.81). Linear regression of the log-transformed EPO values revealed the equation log EPO (mIU/ml) = -0.135 x Hb (g/dl) + 2.821 (r(2) = 0.65). With increasing stages of CKD the correlation between haemoglobin and EPO concentrations was gradually attenuated and was completely lost in CKD stage four and five. In anaemic patients with Hb < 11 g/dl, relative EPO deficiency defined as EPO concentrations below the 25th percentile was present in 38%, 67%, 93% and 100% of the patients with CKD stages 1-5, respectively. CONCLUSIONS: Expression of EPO concentrations in percentiles improves the diagnostic value of measuring EPO concentrations for diagnosing relative EPO deficiency and renal anaemia.     

Optimalization of erythropoietin administration: an Asian perspective

Summary: The efficacy and benefits of recombinant human erythropoietin (r-HuEPO) in the treatment of renal anaemia are well established. Because r-HuEPO therapy is expensive, it is important to optimize its use. It is acceptable to start with a moderate dosage and aim for a moderate rate of response in order to avoid side effects and to reduce costs. the optimal haemoglobin level should be around 12 g/dL; however, in practice, this is often limited to 10 g/dL. Response rate should be around 1 g/dL per month. Subcutaneous administration is the most optimal route and it can be given once or twice weekly.     

Intravenous iron supplementation for the treatment of anaemia in pre-dialyzed chronic renal failure patients.

BACKGROUND: Intravenous iron is a recognized therapy of anaemia in chronic haemodialyzed patients, especially in those receiving erythropoietin (Epo), while its role in the anaemia of pre-dialyzed chronic renal failure (CRF) patients is much less clear. This study attempted to evaluate the effects of intravenous iron in anaemic pre-dialyzed patients. METHODS: Sixty anaemic (haemoglobin<11 g/dl) non-diabetic patients with moderate CRF [32 males, 28 females; mean age 52.2+/-12.5 years; mean glomerular filtration rate 36.2+/-5.2 ml/min], without iron deficiency, iron overload or inflammation, without concomitant erythropoietin treatment and without any previous iron therapy were enrolled. Intravenous iron was administered as iron sucrose, 200 mg elemental iron per month for 12 months, with 1 month pre-study survey and 1 month follow-up after the last iron dose. RESULTS: Intravenous iron supplementation was associated with a significant increase in haemoglobin (from 9.7+/-1.1 at the baseline to 11.3+/-2.5 g/dl after 12 months, a mean increase of 1.6 g/dl), a further 36% of patients reaching the target haemoglobin of 10 g/dl. There was a significant increase in serum iron from 73.9+/-17.2 to 101.8+/-12.2 microg/dl, in serum ferritin from 98.0 (24.8-139.0) to 442.5 (86.0-496.0) microg/l and in transferrin saturation from 21.6+/-2.6 to 33.6+/-3.2%. No worsening of renal function, no increase in blood pressure and no other side effects were noted. CONCLUSIONS: Intravenous iron therapy in pre-dialysis patients with no Epo seems often to ameliorate the anaemia, avoiding the necessity of Epo or blood transfusions in one-third of pre-dialyzed non-diabetic patients. Intravenous iron supplementation appears to be an effective and safe treatment for anaemia in pre-dialysis CRF patients.     

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.     

Haemorheological changes in uraemic children in response to erythropoietin treatment

The increased risk of hypertension during treatment of uraemicpatients with recombinant human erythropoietin (rHuEpo) hasbeen related to increased blood viscosity. We therefore studiedTheological parameters determining whole blood viscosity inseven haemodialysed uraemic children and adolescents duringtreatment with rHuEpo (initial dose 75 IU/kg per week). Beforetreatment the patients were anaemic and had reduced red bloodcell (RBC) deformability at low shear stress of 0.7 Pa in therheoscope compared with six healthy control children (0.14 ±0.03versus 0.19±0.02). The RBC membrane rigidity (i.e. membraneelastic shear modulus) determined in a flow channel was increased(2.04 ±0.26 versus 1.36±0.05 x 10^–5 N/m).After two weeks of rHuEpo, RBC deformability improved and RBCmembrane rigidity decreased significantly. With increasing dosesof rHuEpo the haematocrit rose steadily. After 14 weeks of therapyRBC deformability reached control values, and after 30 weeksRBC membrane rigidity became normal. RBC aggregation and plasmaviscosity were similar in patients and controls and did notchange significantly in response to rHuEpo. The early improvementof RBC deformability may lead to an increase in tissue oxygenationby facilitating microcir-culatory blood flow.     

Integrated therapies including erythropoietin decrease the incidence of dialysis: lessons from mapping the incidence of end-stage renal disease in Japan.

BACKGROUND: Erythropoietin (EPO) has been reported to slow the decline of renal function in predialysis chronic kidney disease (CKD) patients. On the contrary, in the recent large-scale randomized controlled trial (RCT), CREATE and CHOIR, which aimed to keep a higher haemoglobin (Hb) level than former trials, the renoprotective effect of EPO was not observed. Today, the renoprotective effect of EPO has become controversial. In order to test the hypothesis that the usage of EPO in predialysis CKD patients may ameliorate the progression of renal disease, we conducted a macro-level observational study dealing with all Japanese predialysis CKD patients. METHODS: Annually since 1982, the Japanese Society for Dialysis Therapy reports the number of patients that have entered maintenance dialysis in each prefecture of Japan. Based on the 2002-2004 data, we calculated the annual incidence of end-stage renal disease (ESRD) in each of the 47 prefectures. The annual amounts paid for EPO by each prefecture, presumably corresponding to the amounts used, corrected for the estimated predialysis CKD patients, were calculated. We examined the relationship between the incidence of new dialysis and the usage of EPO in each prefecture. Furthermore, the usage of EPO was compared with that of antihypertensive agents including angiotensin converting enzyme inhibitor (ACE-I), and that of statin. RESULTS: There were prefectural differences in the annual incidence of ESRD from 2002 to 2004. We also found prefectural differences in the usage of EPO for the three consecutive years. The usage of EPO in predialysis patients was negatively correlated with the incidence of ESRD on linear and multiple regression analyses. At the same time, the usage of EPO had strong positive correlations with the usage of antihypertensive agents including ACE-I and with that of statin. CONCLUSION: Our nationwide epidemiologic study revealed that a higher use of EPO was associated with a decreased incidence of new dialysis in daily clinical practice. In addition, there were strong correlations among the usage of EPO, antihypertensive agents and statin. These data are supportive of, but do not prove, the hypothesis that EPO may be renoprotective, when used in combination with other strategies.     

Recombinant human erythropoietin therapy in children maintained by haemodialysis

Six children (aged 3 years 11 months to 15 years 9 months) with end-stage renal failure and anaemia (mean haemoglobin 7.1 g/dl, range 6.3–7.7 g/dl) on thrice-weekly haemodialysis were treated with recombinant human erythropoietin (rHuEPO), given as an intravenous bolus in an escalating dose regime after dialysis. All responded with an increase in reticulocyte count and haemoglobin concentration in a mean time of 11 weeks (range 9–13 weeks) and at a dose of 100 or 150 units/kg thrice weekly. The dose of rHuEPO was then adjusted to maintain the haemoglobin concentration within the lower half of the normal range for the child's age and sex. The mean haemoglobin after 12 weeks treatment was 10.9 g/dl (range 8.5–12.1 g/dl) and after 24 weeks, 10.5 g/dl (range 7.9–13.3 g/dl). Four chidlren had no further need for blood transfusion and are thus no longer at risk of blood-borne infection, iron overload and sensitisation to HLA histocompatibility antigens. Serum ferritin fell in the three patients with evidence of iron overload; the three with low or normal iron stores at the onset of treatment maintained erythropoiesis with oral iron supplementation. HLA antibodies decreased in all patients. The only serious complication encountered was thrombosis of vascular access in one child. No child became seriously hypertensive or developed cerebral symptoms. The benefits of rHuEPO therapy for children with end-stage renal failure are potentially considerable and with careful monitoring, the risks low.     

Safety and efficacy of recombinant human erythropoietin treatment of anaemia associated with multiple myeloma in haemodialysed patients

Recombinant human erythropoietin (rHuEpo) was used to treatthe anaemia of four haemodialysed patients (3 males, 1 female)with advanced multiple myeloma; the type of serum M componentwas IgG kappa in all cases. During the 6-month period precedingrHuEpo therapy the patients received multiple blood transfusions(range 4–22 units of packed red cells per patient). Afterthe first month of treatment haematocrit increased from 23±3(SD) to 32±4% and during the last 3 months the maintenancedose of rHuEpo was 143±37 U/kg per week to achieve amean haematocrit of 35±1%. After introduction of rHuEpo,blood transfusions were no longer required and the patientsreported an improvement in wellbeing. No apparent worseningof multiple myeloma has been observed over the treatment periodranging from 5 to 34 months (cumulative duration of treatment55 months). Anti-hypertensive therapy was started in one caseand increased in two patients. We conclude that rHuEpo appearsto be effective and safe in treating anaemia associated withmultiple myeloma in patients requiring haemodialysis.