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)     

Effect of erythropoietin on urinary liver-type fatty-acid-binding protein in patients with chronic renal failure and anemia

BACKGROUND/AIM: The urinary liver-type fatty-acid-binding protein (L-FABP) level reflects the clinical progression of chronic kidney disease. We conducted a study to determine whether administration of erythropoietin (EPO), which is produced in response to hypoxic stress, affects urinary protein excretion and L-FABP levels in patients with chronic renal failure (CRF) and anemia. METHODS: The study was an interventional trial that included 20 anemic CRF patients (median serum creatinine level 2.0 mg/dl, range 1.3-2.9 mg/dl; median hemoglobin concentration 9.2 g/dl, range 8.2-9.8 g/dl; median estimated glomerular filtration rate 20.5 ml/min, range 15.0-28.0 ml/min; group A). Recombinant EPO (12,000 U twice/month) was given to these patients for 6 months. Urinary protein, L-FABP, 8-hydroxy-2'-deoxyguanosine, and hemoglobin levels were measured before and 3 and 6 months after treatment. Twenty nonanemic CRF patients were enrolled as controls (group B). RESULTS: After 6 months, the hemoglobin level was increased as compared with the baseline level in group A treated with EPO (median 11.3 g/dl, range 9.3-13.8 g/dl, vs. median 9.2 g/dl, range 8.2-9.8 g/dl; p < 0.01) but not in the untreated group B (median 11.8 g/dl, range 10.2-13.0 g/dl, vs. median 12.1 g/dl, range 10.8-13.4 g/dl; not significant). The urinary protein excretion was decreased as compared with the baseline level in group A (median 1.2 g/day, range 0.6-1.9 g/day, vs. median 1.9 g/day, range 1.1-2.6 g/day; p < 0.01) but not in group B (median 1.4 g/day, range 0.7-2.2 g/day, vs. median 1.6 g/day, range 0.7-2.3 g/day; not significant). The urinary L-FABP level was also decreased as compared with the baseline level in group A (median 50.0 microg/g creatinine, range 7.5-90.0 microg/g creatinine, vs. median 115.0 microg/g creatinine, range 20.0-225.0 microg/g creatinine; p < 0.01) but not in group B (median 82.0 microg/g creatinine, range 15.5-158.0 microg/g creatinine, vs. median 76.0 microg/g creatinine, range 25.0-138.5 microg/g creatinine; not significant). The glomerular filtration rate changed little throughout the study period in either group. The urinary 8-hydroxy-2'-deoxyguanosine level was decreased as compared with the baseline level in group A (median 22.0 ng/mg creatinine, range 8.0-30.0 ng/mg creatinine, vs. median 38.5 ng/mg creatinine, range 14.0-68.0 ng/mg creatinine; p < 0.01) but not in group B (median 33.0 ng/mg creatinine, range 9.0-56.0 ng/mg creatinine, vs. median 30.0 ng/mg creatinine, range 10.0-54.0 ng/mg creatinine; not significant). CONCLUSION: EPO supplementation may ameliorate renal tubular damage, in part, due to a reduction of oxidative stress in CRF patients with anemia.     

Effect of renal replacement therapy on cellular cytokine production in patients with renal disease

To evaluate the effect of renal replacement therapy on cellular cytokine production in patients with renal disease, we studied interleukin 1 (IL-1) and interleukin-2 (IL-2) production by target cells stimulated with supernatants from cultured peripheral blood mononuclear cells from patients with end-stage renal disease, who were treated with hemodialysis and continuous ambulatory peritoneal dialysis (CAPD) before and after hemodialysis or a peritoneal dialysate exchange, compared to normal subjects used as time controls, and patients with chronic renal insufficiency. Initial cellular IL-2 production was increased in patients with hemodialysis, compared to normal controls. The ratio of pretreatment cellular IL-2 and IL-1 production was increased in all patient groups compared to normal subjects. Both hemodialysis and CAPD treatments resulted in increased cellular IL-1 (51.7%, P less than 0.007, and 42.8%, P less than 0.002, respectively) and IL-2 production (50.5%, P less than 0.015, and 33.3%, P less than 0.0008, respectively). The hemodialysis group had significantly higher cellular IL-2 production compared with normal controls' after treatment. After treatment, the IL-2/IL-1 ratio remained elevated in all groups with renal disease compared with normal subjects. We conclude patients with renal disease have an abnormal functional relationship between IL-1 and IL-2, characterized by increased IL-2 production per level of IL-1, unaffected by type or presence of renal replacement therapy.     

Evidence for renal vasodilation in pre-dialysis patients during correction of anemia by erythropoietin.

Results from animal experiments have suggested that treatment with recombinant human erythropoietin (rHuEPO) causes changes in renal hemodynamics which are detrimental to renal function. Therefore, the effects of correction of the anemia by rHuEPO on glomerular filtration rate (GFR; inulin clearance) and effective renal plasma flow (ERPF; PAH clearance) were studied in eight pre-dialysis patients. The studies were done before (Hct 0.24 +/- 0.05 liter/liter) and at 89 +/- 19 days after the start of rHuEPO therapy (Hct 0.39 +/- 0.03 liter/liter). To further evaluate the effects of ACE inhibition, 25 mg of captopril was given orally after baseline values had been obtained. Baseline GFR, renal blood flow (RBF) and filtration fraction (FF) did not change during rHuEPO therapy. At low hematocrit (Hct) captopril induced a significant increase in ERPF and RBF, and a decrease in MAP. After correction of the hematocrit the blood pressure lowering effect of captopril remained unchanged. However, captopril no longer induced changes in ERPF and RBF. We conclude that the increase in hematocrit had no adverse effects on GFR. The results suggest that changes in hematocrit may influence the effects of ACE inhibition on efferent vascular resistance. Therefore, the hematocrit should be taken into account when evaluating studies on the effects of ACE inhibition in the progression of chronic renal failure.     

Possible role of soluble erythropoietin receptors in renal anemia

Recombinant human erythropoietin(rHuEpo) is effective for the treatment of renal anemia associated with chronic renal failure(CRF). However, we have encountered some patients with CRF who have sometimes developed a resistance to rHuEpo. This resistance can be due to iron or folate deficiency, aluminum toxicity, hyperparathyroidism, or auto-antibodies for rHuEpo. In this study, we focused on the soluble erythropoietin receptor(sEpoR), which can bind to rHuEpo. To demonstrate the possibility that the sweeping of rHuEpo by sEpoR results in resistance to rHuEpo, we performed a bioassay using the rHuEpo-dependent cell line, UT7/EPO. The results showed that recombinant mouse sEpoR(rmsEpoR) can reduce the proliferation of UT7/EPO induced by rHuEpo in a dose-dependent manner. We consider that this cell line could be a useful tool in a bioassay to detect the inhibitory factor(s) against Epo. We selected sera from three groups of patients with renal anemia associated with CRF who were receiving hemodialysis three times a week: the first was a patient group that needed a high dose of rHuEpo(7,500-9,000 unit/dialysis), the second was a patient group that needed an intermediate dose of rHuEpo (4,500 unit/dialysis), the third was a patient group that needed a low dose of rHuEpo(below 1,500 unit/dialysis). Interestingly, the proliferation of UT7/EPO determined with [3H]-thymidine incorporation was reduced by the addition of sera from the first group, but not by the addition of sera from the third group. These results suggested that serum sEpoR may play an important role in signal transduction via EpoR on erythroid progenitor in CRF patients.     

Effect of renal dialysis therapy modality on T cell cytokine production.

INTRODUCTION: Dialysis has been associated with acute changes in the complement activation status, granulocyte markers, macrophage function, T cell activation and the release of pro-inflammatory cytokines. The most common analysis of cytokine production in patients on dialysis has focused on the changes in monokines (particularly IL-1 and TNF alpha), however it is becoming clear that T cell cytokines play a major role in the impaired lymphocyte function of dialysis patients. METHODS: To assess the effect of dialysis modality on T cell function we analysed the ability of T cells within peripheral blood mononuclear cell populations (PBMC) to produce cytokines after mitogen (phorbol-12-myristate-13-acetate; PMA and lonomycin; I) stimulation in patients on peritoneal dialysis (PD) compared to low flux haemodialysis (HD) and normal individuals (controls). RESULTS: In control PBMC, PMA + I stimulation significantly increased the percentage of CD3+ cells expressing IL-2, IFN gamma, TNF alpha, IL-4 and IL-10, as expected. However, although mitogen stimulation significantly enhanced the percentage of the classical Th1 cytokines (IL-2, IFN gamma and TNF alpha) in the low flux HD PBMC, it had no effect on CD3+ IL-2 or CD3+ TNF alpha producing cells in the PD group. In contrast, the percentage of T cells producing Th2 cytokines (IL-4 and IL-10) could not be consistently enhanced by mitogen in either dialysis group. CONCLUSIONS: We suggest that PD alters the ability of T cells to produce cytokines, possibly by causing an 'exhaustion' of the Th1 cells, thereby preventing cells to produce cytokine on ex vivo stimulation. Furthermore, since T cells from both low flux HD and PD groups could not be induced to produce Th2 cytokines we suggest that uraemia or dialysis per se inhibits T cells from producing Th2 cytokines.     

Endogenous erythropoietin levels and anemia in long-term renal transplant recipients

BACKGROUND/AIM: Although anemia is a common complication after renal transplantation (RT), data concerning endogenous erythropoietin (EPO) levels in long-term RT recipients are rare. The goal of this study was to evaluate the prevalence of anemia within 6 months to 5 years after RT and to assess the relationship between the serum concentrations of endogenous EPO, graft function and grade of improvement of anemia. METHODS: 140 patients who had undergone RT were included in the group: 89 males (63.6%) and 51 females (36.4%), with an average age 46.8 +/- 12.8 years. The serum concentrations of EPO and creatinine (Cr) were tested in all the individuals and the values of the red blood component of blood count, serum ferritin (SF), plasma iron concentration, plasma total iron-binding capacity (TIBC), transferrin saturation (TS), folic acid and vitamin B(12) levels in the serum were determined. A statistical analysis of the results was performed using the correlation analysis, Mann-Whitney U test and Duncan's multiple range test. RESULTS: Normal blood count values were found in 91 patients (65%), and a mild grade of anemia with a mean hemoglobin (Hb) 114.4 +/- 11.9 g/l was observed in 45 patients (32.1%), and 4 patients (2.9%) fulfilled the diagnostic criteria for post-transplantation erythrocytosis. Individuals with normal Hb values had a mean EPO serum concentration of 39.3 +/- 12.3 mU/ml (median 37.2) and the mean Cr was 133.8 +/- 36.9 micromol/l (median 122). Patients with anemia (Hb <120 g/l in females, Hb <130 g/l in males) had a mean EPO value of 47.0 +/- 26.6 mU/ml (median 36.0) and a mean Cr of 203.8 +/- 108.9 micromol/l (median 181). The difference in the Cr values was statistically significant (p < 0.0001), while the difference between the EPO concentrations was not significant. No relation of EPO serum concentration with regard to graft function was found in the analysis. A lack of storage iron (SF <10 microg/l in females, SF <22 microg/l in males) was found in 16 patients (11.4%), and a lack of functional iron (TS <20%) was found in 27 patients (19.3%). CONCLUSIONS: Theprevalence of anemia in patients after transplantation was 32.1%. The most common cause of anemia is insufficient graft function development. The achieved values of the red component of blood count have no relation to the endogenous EPO serum concentrations.     

重组人促红细胞生成素治疗肾性贫血的疗效分析

目的观察重组人促红细胞生成素（rHuEPO）治疗慢性。肾衰竭患者贫血的疗效。方法选择我院慢性肾衰竭患者42例,分为2组,其中慢性肾衰竭维持性血液透析患者21例为血液透析组（HD组）,慢性肾衰竭维持性腹膜透析患者21例为腹膜透析组（PD组）。所有慢性肾衰竭患者分别于入组后的第1天、3个月、6个月测定血红蛋白（Hb）、红细胞计数（RBC）、血细胞比容（Hct）、网织红细胞计数（Ret）、全段甲状旁腺素（iPTH）和促红细胞生成素（EPO）水平。结果①治疗前,2组间Hb、RBC、Hct、Ret、iPTH和EPO无统计学差异（P〉0．05）。②治疗后第3个月,HD组Hb、Hct低于PD组（P〈0．05）,iPTH高于PD组（P〈0．05）。③治疗后第6个月,HD组Hb、Hct、iPTH与PD组相比无显著性差异（P〉0．05）。④相关分析表明,慢性肾衰竭患者Hb与iPTH呈负相关（r=-0．81,P〈0．05）,与RBC、Hct和Ret呈正相关（r分别为0．79、0．91、0．59,P〈0．05）,与EPO水平无相关性（P〉0．05）。结论慢性肾衰竭患者的贫血程度与甲状旁腺功能有关。rHuEPO治疗早期,腹膜透析较血液透析更容易改善患者的贫血状况,可能与前者较好的清除血iPTH有关,但随着治疗时间的延长,腹膜透析此方面的优势不再明显。     

Effect of erythropoietin on anemia of peritoneally dialyzed anephric rats

The effect of erythropoietin on anemia was studied in anephric rats undergoing peritoneal dialysis. Both the number of bone marrow red cell precursors and plasma iron turnover were markedly depressed in untreated peritoneally dialyzed anephric animals when compared to peritoneally dialyzed sham-operated control rats. Anephric rats receiving 2 U of erythropoietin per day for 12 days had greater than threefold more bone marrow red cell precursors and a twofold larger plasma iron turnover than did the saline injected anephric rats. There was no significant difference in either bone marrow red cell precursors or plasma iron turnover in the erythropoietin-treated anephric rats when compared to the nonuremic controls. Although the rats receiving erythropoietin for 12 days had a significantly higher hematocrit (29.5%) than the saline injected uremic rats did (19.0%), the hematocrit was significantly lower than that found in nonuremic control animals, either receiving erythropoietin (48.1%) or not receiving erythropoietin (41.6%). Our data suggests that erythropoietin is potentially a useful agent for the treatment of anemia of chronic renal failure.     

Recombinant erythropoietin rapidly treats anemia in ischemic acute renal failure

BACKGROUND: The anemia associated with acute renal failure (ARF) is currently treated with blood transfusions, while the anemia of chronic renal failure is treated with recombinant erythropoietin (EPO). We hypothesized that EPO treatment during ARF could rapidly improve hemoglobin levels and be a useful therapeutic approach. In addition, as tubular epithelial cells have EPO receptors that can mediate proliferation, enhanced recovery of renal function may occur with EPO use. METHODS: An established rat model of ischemic ARF was studied, using either moderate or severe ischemia. EPO was administered in a dose of 500 or 3000 U/kg starting at time of ischemia. Hematocrit (Hct), serum creatinine, reticulocyte count, and mortality rate were measured. RESULTS: EPO treatment led to a rapid and significant increase in Hct at 48 and 72 hours after moderate ischemic renal reperfusion injury (IRI) in EPO (500 U/kg)-treated rats compared with control (saline treated) rats (mean +/- SE; 45.6 +/- 0.3% vs. 42.0 +/- 1.0%, P < 0.01) and (46.6 +/- 0.3 vs. 41.0 +/- 1.0, P < 0.01, N = 3 per group). In severe renal IRI, EPO treatment also led to significantly increased Hct at 48 (40.0 +/- 4.4% vs. 36.8 +/- 0.3%, P < 0.01, N = 3 per group) and 72 hours (43.5 +/- 1.5% vs. 34.7 +/- 2.3%, P < 0.01, N = 3 per group). Higher dose (3000 U/kg) EPO led to a more pronounced Hct increase after severe IRI at 48 hours compared with the 500 U/kg dose (43.5 +/- 0.3 vs. 40.3 +/- 0.3, P < 0.01, N = 3 per group). EPO treatment during moderate or severe renal IRI did not change the course of the renal dysfunction. EPO treatment (N = 19) had a significant protective effect on mortality during severe IRI. In addition, loss of body weight during ARF was not affected by EPO therapy. CONCLUSIONS: Recombinant EPO can rapidly increase Hct and improve mortality during ARF. Human studies are warranted to evaluate the clinical applicability of this important finding.     

Mechanisms of erythropoietin production in renal cell carcinoma

In-vitro and in-vivo experiments performed to determine the mechanisms of erythropoietin (EPO) production in renal cell carcinoma are reviewed. When a human EPO-producing renal cell carcinoma was transplanted into athymic nude mice, EPO produced by the renal cell carcinoma cells autonomously produced erythrocytosis that did not respond to physiologic stimuli. Although expression of the EPO gene was detected in EPO-producing renal cell carcinoma, no structural alterations were evident in the EPO gene in this carcinoma. The exact mechanism underlying EPO production at the genetic level remains unknown. EPO production in renal cell carcinoma is thought to be heterogeneous and to be affected by various cytokines. Received: May 13, 1999 / Accepted: July 13, 2000     

Bone marrow changes following treatment of renal anemia with erythropoietin.

In 14 severely anemic patients with end-stage renal disease and chronic hemodialysis the effect of recombinant human erythropoietin (EPO) on hemopoiesis was investigated. Bone marrow biopsies were taken before and after four and 26 months of treatment with EPO to evaluate quantitative and qualitative changes of histomorphology. EPO induced normalization of maturation and an increase in cell mass of the erythropoietic line in all patients. The number of megakaryocyte also increased significantly with EPO treatment (P less than 0.01). At the time of the third bone marrow biopsy (26 months) erythropoiesis was normal. Megakaryopoiesis remained unchanged compared to the second biopsy (4 months). No cytomorphologic abnormalities or other evidence for malignant disorder could be detected in any of the patients. Hematocrit increased from a mean of 19 to 31 percent at the second evaluation (P less than 0.001). Platelet count had risen by a mean of 30,000 at four months (P less than 0.05) and slightly decreased at 26 months. These observations suggest great safety of long-term treatment with recombinant human erythropoietin, and demonstrate efficacy in correcting reduced and immature erythropoiesis in chronically hemodialyzed patients. EPO also stimulates human megakaryopoiesis.     

Effects of reduction of renal mass on renal oxygen tension and erythropoietin production in the rat

BACKGROUND: It is well known that the anemia of chronic renal failure is associated with a blunted erythropoietin response. However, it is not clear why this response is blunted. Oxygen tension is an important regulator of erythropoietin production and release, but the effect of reduced renal mass on renal tissue oxygen tensions is currently unknown. METHODS: A computer-based simulation was used to determine how alterations in filtration fraction might impact on renal tissue oxygen tensions. In addition, direct measurements of oxygen tension with needle electrodes were employed, as well as conventional physiological measurements and ELISA measurements of plasma and tissue erythropoietin concentrations in rats subjected to 5/6th nephrectomy. RESULTS: Remnant kidney rats had 39% and 52% decreases in tissue and plasma erythropoietin concentrations, respectively, that correlated with 73% increased oxygen tensions in both cortex and outer medulla in the remnant kidney (all P < 0.01). Estimations of filtration fraction were decreased by approximately 36% in the rats bearing remnant kidneys. CONCLUSIONS: Higher oxygen tensions were observed in the remnant kidneys. We suggest that higher oxygen tensions are caused by a decrease in filtration fraction, and that these higher tissue oxygen tensions result in decreased renal erythropoietin production and anemia.     

慢性肾衰患者血红蛋白浓度变化对血清细胞因子活性的影响作用

目的为了探讨贫血与慢性肾衰（ＣＲＦ）免疫功能状态的关系。方法检测了ＣＲＦ患者单纯输血及用红细胞生成素（ＥＰＯ）治疗前后细胞因子白细胞介素２（ＩＬ２）、可溶性白细胞介素２受体（ｓＩＬ２Ｒ）、肿瘤坏死因子（ＴＮＦ）及γ干扰素（γＩＦＮ）水平，并与肾功能正常肾小球肾炎患者（ＧＮ）组及对照组（Ｃ）进行比较分析。结果ＣＲＦ组血清ＩＬ２，ＴＮＦ和γＩＦＮ水平均显著低于ＧＮ组及Ｃ组（Ｐ＜００１），ｓＩＬ２Ｒ水平则较ＧＮ组及Ｃ组明显升高（Ｐ＜００１）。ＣＲＦ组血清ＩＬ２，ＴＮＦ和γＩＦＮ水平与血红蛋白浓度存在直线正相关，而ｓＩＬ２Ｒ水平与血红蛋白浓度呈负相关性，单纯输血或应用ＥＰＯ治疗能改变这些细胞因子活性水平。结论ＣＲＦ免疫功能低下与贫血有关，及时治疗和改善贫血状态可部分纠正这种免疫异常。     

Improved physical performance after treatment of renal anemia with recombinant human erythropoietin

The physical performance of 12 anemic patients on renal dialysis was investigated following treatment of renal anemia with recombinant human erythropoietin (rhEPO; 40-120 U/kg, 3 times a week). Exercise intensity at a heart rate of 130 beats/min (PWC130) on a bicycle ergometer was assessed before rhEPO treatment, after reaching the target hematocrit (73 +/- 18 days), and in the maintenance phase (211 +/- 53 days). Hemoglobin concentrations measured at these time points were 7.3 +/- 1.2, 11.9 +/- 1.5, and 12.1 +/- 1.4 g/dl, respectively. PWC130 rose from 77 +/- 27 to 104 +/- 37 and 104 +/- 51 W, respectively. Aerobic threshold (i.e. blood lactic acid concentration of 2 mmol/l) shifted to higher workloads indicating improved muscle oxygen supply.