rHuEPO Requirements Research Articles

Correlation Between Recombinant Human Erythropoietin Dose and Inflammatory Status in Dialysed Patients

Once recombinant human erythropoietin (r-HuEPO) was introduced in daily practice, huge steps were made in combating the adverse effects induced by anemia in chronic kidney disease population. Still, r-HuEPO resistance and the doses ensuring the maximum therapeutic benefit remain matters of debate. The aim of our study was to assess the correlation between the presence and the degree of inflammation and the r-HuEPO requirements in chronic dialysis patients. We conducted a 2 years prospective study on 146 patients undergoing chronic dialysis treated with r-HuEPO. Based on their average CRP (C-reactive protein) levels, obtained from repeated samplings at 3 months interval, 3 groups were formed; we noted in each group the average values of r-HuEPO prescribed to achieve the optimum hemoglobin levels according to the dialysis best practice guidelines and all the adverse effects of the therapy. A direct correlation was observed between CRP levels and r-HuEPO requirements in the first 2 groups of patients (CRP under 6 mg/L and CRP values 6-20 mg/L), with significant increase in r-HuEPO doses between groups (p [ 0.001); the third group, CRP values over 20 mg/dL, showed a minor, insignificant increase in average r-HuEPO doses compared to mild inflammation group (p = 0.199) and more adverse effects of the therapy (p [ 0.05). Inflammation is an important determinant of anemia in chronic dialysis patients and can induce an increase in the doses of r-HuEPO. However, prescribing excessive r-HuEPO doses is not the answer in severe inflammatory status, due to lack of response and possible adverse effects.

The Efficacy of Intravenous versus Subcutaneous Recombinant Erythropoietin in Obese African-African Patients in a Southeast U.S. Dialysis Cohort

Aims: To correct renal anemia, subcutaneous (SC) route of recombinant human erythropoietin (rhuEPO) administration has been associated with increased efficacy and decreased dose requirements, when compared with intravenous (IV) route. The effect of obesity as a potential modifier during rhuEPO administration has not been well explored. Study Design: Single-center, Longitudinal Cohort Study. Place and Duration of Study: University of Mississippi Medical Center Outpatient Dialysis Unit, between February and November of 2009. Research Article British Journal of Medicine & Medical Research, 4(1): 184-193, 2014 185 Methodology: We performed IV to SC rhuEPO conversion for 86 in-center dialysis patients and, following a six-month equilibration period, we monitored outcomes over a period of three months. We obtained baseline demographic parameters, calculated Body Mass Index (BMI) and monitored iron saturation, ferritin, hemoglobin (Hgb) along with rhuEPO requirements. Patients were divided into 3 categories based on BMI [ 35 (n= 21) kg/m]. Results are reported either as percents, means with SD or median with 25-75% interquartile range, as appropriate. Results: The cohort was all African-American, 48.8% male, aged 54.7 (13.3) years and BMI calculated at 29.9 (7.4) kg/m. Baseline iron saturation was 24 (10.6)%, ferritin measured 641 (277) ng/mL. Hgb remained unchanged during the observation period: 11.1 (1.3) vs. 11.2 (1.3) gm/dL. Initial rhuEPO weekly dose for the entire cohort was 19,729 (17,448) Units/week (U/week); final dose 17,482 (14,860) U/week, with close correlation between initial and final doses (r: 0.653, P<0.0001). Weekly rhuEPO dose remained virtually unchanged in BMI categories 1 and 2 [13,927 (10,938) vs. 13,297 (10,247) U/week; 20,684 (15,788) vs. 20,997 (17.917)] (P=NS for both) but decreased in the category 3: 25,459 (24,403) vs. 16,444 (12,749) (P=0.081). However, BMI had no independent effect in linear regression modeling with multiple covariates (age, BMI, iron saturation, ferritin) included. Conclusion: Obesity may affect relative efficacy of rhuEPO conversion; additional studies may be needed.

Dialysis Patients With the Metabolic Syndrome Need Less Recombinant Human Erythropoietin for Similar Hemoglobin Levels

IntroductionThe metabolic syndrome (MS) components, such as dyslipidemia, prothrombotic status, and increased blood pressure, are risk factors for patients with renal disease. Visceral fat mass is closely related to the MS and atherosclerosis. We investigated the effects of body compositions and MS on anemia parameters and recombinant human erythropoietin (rHuEPO) requirements in maintenance hemodialysis patients. MethodsBody composition (body mass index and bioimpedance analysis) and laboratory data were obtained from 110 dialysis patients. The MS was identified according to ATP-III criteria. Anemia parameters, hemoglobin (Hgb), albumin, C-reactive protein (CRP), calcium, phosphorus, parathormone levels, and rHuEPO requirements over the last 6 months were retrospectively analyzed. ResultsPatients with the MS seem to reach target Hgb levels more frequently (10–12 g/dL; 66.3% vs 84.8%; P = .03) without any difference in total intravenous iron therapy dosage. MS patients also required lower rHuEPO for reaching similar Hgb levels compared with patients without MS (2679.3 ± 1936.1 vs 3702.5 ± 2213.0 U/kg/6 mo; P = .02). There were no differences in serum CRP, albumin, or Hgb levels between the 2 groups (P > .05). We observed that patients with MS had significantly higher fat mass and visceral fat ratio, but similar muscle mass values compared with no-MS counterparts (P = .0001 and .001, respectively). However, when we compared the ratios of these parameters we observed a significant reduction in muscle ratios and a significant increase in fat ratios of MS patients (P = .0001). ConclusionOur results indicate that MS might be an advantage for reaching higher Hgb levels with lower rHuEPO dosages. The possible reason for this might be the good nutritional state and increased fat mass of patients with MS.

RHuEPO Hyporesponsiveness and Related High Dosages Are Associated with Hyperviscosity in Maintenance Hemodialysis Patients

Objective. Increased viscosity may increase the risk of thrombosis or thromboembolic events. Recombinant human erythropoietin (rHuEPO) is the key stone treatment in anemic ESRD patients with the thrombotic limiting side effect. We evaluated the influence of clinical and laboratory findings on plasma viscosity in MHD patients in the present study. Method. After applying exclusion criteria 84 eligible MHD patients were included (30 female, age: 54.7 ± 13.7 years). Results. Patients with high viscosity had longer MHD history, calcium × phosphorus product, and higher rHuEPO requirement (356.4 versus 204.2 U/kg/week, P: 0.006). rHuEPO hyporesponsiveness was also more common in hyperviscosity group. According to HD duration, no rHuEPO group had the longest and the low rHuEPO dosage group had the shortest duration. Despite similar Hb levels, 68% of patients in high rHuEPO dosage group; and 38.7% of patients in low rHuEPO dosage group had higher plasma viscosity (P: 0.001). Patients with hyperviscosity had higher rHuEPO/Hb levels (P: 0.021). Binary logistic regression analyses revealed that rHuEPO hyporesponsiveness was the major determinant of hyperviscosity. Conclusion. We suggest that the hyperviscous state of the hemodialysis patients may arise from the inflammatory situation of long term HD, the calcium-phosphorus mineral abnormalities, rHuEPO hyporesponsiveness, and related high dosage requirements.

Evaluation of the impact of a new synthetic vitamin E-bonded membrane on anemia and rHuEPO requirement in ESRD patients with central venous catheters: a pilot study

In the last years, the number of hemodialysis (HD) patients with erythropoietin (rHuEPO) resistance is increasing. Probably, central venous catheters (CVCs) contribute to this resistance by inducing inflammation and oxidative stress. This study was aimed to compare vitamin E-bonded dialyzer (PSVE) versus polyethersulfone membrane. Sixteen subjects with CVCs were included in a prospective two-arm crossover 12-month study. The primary endpoints were the rHuEPO requirement and the erythropoiesis-stimulating agents (ESA) index, which was defined by the ratio between weekly EPO dosage (IU/kg/week) and Hb levels (g/dl). The mean dosages of rHuEPO to maintain hemoglobin between 10.5 and 12 g/dl were 135 ± 59 and 101 ± 57 IU/kg/week with polysulfone and PSVE, respectively (P = 0.14). The ESA indexes were 12.1 ± 5.2 and 8.7 ± 5.2 (P < 0.0001) with polysulfone and PSVE, respectively. A trend towards consensual changes in protein glycoxidation, antioxidant, and inflammatory markers was observed. In conclusion, the study suggests a role for PSVE in the reduction of ESA index in HD patients with CVCs.

The Influence of Hepatitis C Infection Activity on Oxidative Stress Markers and Erythropoietin Requirement in Hemodialysis Patients

We sought to expose the possible effect of hepatitis C virus (HCV) infection on oxidative stress indicators, nutritional status, and erythropoietin (rHuEPO) requirements in maintenance hemodialysis (MHD) patients. A total of 111 MHD patients (69 males, 42 females; mean age 51.3 ± 13.0 years; MHD duration 78.5 ± 52.1 months) and 46 healthy controls were enrolled in the study. We excluded patients with hepatitis B infection or malignancy. Indicators for oxidative status were studied in plasma samples obtained at the beginning of a clinically stable MHD session. Measurements were performed for plasma superoxide dismutase, glutathione peroxidase (antioxidative agents), and malonyldialdehyde (MDA; oxidative agent) by spectrophotometric methods. All patients were analyzed for the presence of anti-HCV; positive patients were also evaluated for the presence of HCV RNA. MHD patients were divided into three groups according to HCV infection status: group I (anti-HCV-positive, HCV-RNA-negative; n = 22); group II (anti-HCV-positive, HCV-RNA-positive; n = 22), and group III (anti-HCV-negative; n = 67). According to the analyses, MHD patients showed higher plasma oxidative stress indicators and lower antioxidative indicator levels compared to controls ( P < .0001). MHD patients also displayed lower albumin and higher C-reactive protein (CRP) levels compared to controls ( P < .0001). Antioxidant levels were decreased significantly from group I to III ( P < .0001). MDA levels significantly increased from group I to III ( P < 0.01). HCV-RNA-positive patients showed lowest albumin and highest CRP levels and rHuEPO requirements. Although alanine transferase (ALT) levels were in the normal range, group II patients had significantly higher ALT levels than the other groups ( P < .01). In conclusion, we observed negative effects of active HCV infection on oxidative stress and rHuEPO requirements. In contrast, we detected that clinically inactive HCV infection was associated with reduced oxidative stress and rHuEPO requirements compared with active HCV infection and HCV-negative patients.

Ascorbic acid and erythropoietin

I read a recent publication by Philipneri and colleagues with great interest.1. The authors reached the conclusion that “the role of ascorbic acid in reducing the erythropoietin requirement appears promising.”1. Indeed, the use of ascorbic acid in patients requiring hemodialysis is mentioned in another study.2. Biesalski said that “parenteral administration of ascorbic acid may be an approach that can overcome problems of vitamin C deficiency in hemodialysis patients.”2. However, the correlation of vitamin C and hemodialysis is not mentioned in this work.2. In a recent meta-analysis by Deved and colleagues, it was reported that, “compared with standard care, ascorbic acid use may result in an increase in hemoglobin concentration and transferrin saturation and decrease in rHuEPO requirements.”3. However, the problems of the small number of study participants and the short follow-up time were also noted.3. To reach the finalized conclusion that ascorbic acid helps decrease the requirement of erythropoietin in hemodialysis, there is a need to verify the direct physiological correlation between vitamin C and erythropoietin.

Ascorbic Acid for Anemia Management in Hemodialysis Patients: A Systematic Review and Meta-analysis

Ascorbic acid is believed to improve anemia in patients with end-stage renal disease, but its overall effectiveness is unclear. Systematic review and meta-analysis. Adult hemodialysis patients. Randomized clinical trials of ascorbic acid use in addition to standard anemia management. Ascorbic acid. Weighted mean difference (WMD) for change in hemoglobin level, recombinant human erythropoietin (rHuEPO) dose, transferrin saturation and ferritin level and adverse events. Of 157 potentially relevant studies, 6 studies (n = 326 patients) met the inclusion criteria. Combining the 3 randomized clinical trials involving patients with baseline hemoglobin levels <11 g/dL, change in hemoglobin level was greater for ascorbic acid use compared with standard care (WMD, 0.9 g/dL; 95% CI, 0.5-1.2 g/dL). Compared with standard care, ascorbic acid use also was associated with a statistically significant decrease in rHuEPO dose (WMD, -17.1 U/kg/wk; 95% CI, -26.0 to -8.2 U/kg/wk) and improvement in transferrin saturation (WMD, 7.9%; 95% CI, 5.2-10.5%), with no change in ferritin concentration. Adverse events had questionable relevance to ascorbic acid use; no study reported oxalate levels or occurrence of oxalosis. Small number of studies, heterogeneity between study populations, and study durations were short. Adverse events were poorly reported. Although the studies are limited by small numbers of subjects, short durations of follow-up, and variable quality, these results suggest that compared with standard care, ascorbic acid use may result in an increase in hemoglobin concentration and transferrin saturation and decrease in rHuEPO requirements. Longer term studies are required to confirm these results, provide information about adverse events, and determine whether these changes translate into improved patient outcomes and cost-effectiveness.

The importance of low blood urea nitrogen levels in pregnant patients undergoing hemodialysis to optimize birth weight and gestational age

Most published reports indicate that intensified hemodialysis results in better pregnancy outcomes. Here we studied clinical characteristics and the outcomes of 28 pregnant women receiving hemodialysis. We found an association between maternal blood data and birth weight, and gestational age and outcomes. There were 18 surviving infants who were followed up for one year. In the others there were 4 spontaneous abortions, 1 stillbirth, 3 neonatal deaths and 2 deaths after birth. Analysis of blood chemistry for 20 pregnancies from 12 weeks of gestation until delivery showed that the average hemoglobin level was significantly higher in the group that successfully delivered than in the unsuccessful group. There were significant negative relationships between the blood urea nitrogen (BUN) level and the birth weight or gestational age in the latter cohort. A birth weight equal to or greater than 1500 g or a gestational age equal to or exceeding 32 weeks corresponded to BUN levels of 48-49 mg/dl or less. Whether the low BUN is the direct cause of the improved outcome remains to be examined.

Endogenous plasma carnitine pool composition and response to erythropoietin treatment in chronic haemodialysis patients

Anaemia is a common complication associated with haemodialysis and is usually managed by treatment with recombinant human erythropoietin (rHuEPO). However, many patients remain hyporesponsive to rHuEPO treatment despite adequate iron therapy. The effect of L-carnitine administration on rHuEPO dose and/or haematocrit in haemodialysis patients has been previously reported with equivocal results. This study examined the relationship between endogenous carnitine pool composition and rHuEPO requirements in long-term haemodialysis patients. Pre-dialysis blood samples were collected from 87 patients and analysed for plasma L-carnitine and individual acylcarnitine levels by LCMS/MS. As an indication of rHuEPO responsiveness, erythropoietin resistance index (ERI) was calculated as rHuEPO dose/kg/week normalized for haemoglobin levels. A significant negative correlation between L-carnitine levels and ERI was found (P = 0.0421). All patients categorized as high ERI (>0.02 microg/kg/week/gHb) exhibited subnormal L-carnitine levels (<30 microM); conversely, patients with normal L-carnitine levels (>30 microM) displayed low ERI values (<0.02 microg/kg/week/gHb). More importantly, the ratio of non-acetyl acylcarnitines/total carnitine was significantly positively correlated with ERI (P = 0.0062). These data illustrate the relationship between carnitine levels and response to rHuEPO treatment in haemodialysis patients, in particular, the importance of the proportion of long-chain acylcarnitines within the plasma carnitine pool. This proportion may be more indicative of the response to L-carnitine supplementation than absolute L-carnitine levels alone.

Effect of Vitamin E-Coated Dialysis Membranes on Anemia in Patients with Chronic Kidney Disease: An Italian Multicenter Study

Increased oxidant stress is increasingly recognized as a crucial factor in anemia in patients with chronic kidney disease. Vitamin E-coated membranes (VECMs) consist of a multilayer membrane with liposoluble vitamin E on the blood surface allowing direct free radical scavenging at the membrane site, which is of potential clinical benefit. Our objective was to examine the effect of VECMs on anemia in chronic hemodialysis (HD). We enrolled 172 stable chronic HD patients (94 men, 78 women, age 65.4 +/- 13.4 years) in an open-label multicenter study. They were shifted from their previous dialyzer to VECM for 1 year. Hemoglobin (Hb) levels and recombinant human erythropoietin (rHuEpo) dosage were analyzed after 4, 8, and 12 months on the VECM and compared with baseline values using paired tests. Hb significantly increased from 10.9 +/- 1.2 g/dL at baseline to 11.7 +/- 1.2 g/dL after 12 months (p<0.001) on VECMs. Conversely, the rHuEpo dosage decreased from 7,762 +/- 5,865 IU/week at baseline to 6,390 +/- 5,679 IU/week after 12 months (p<0.001). The proportion of patients who were at target Hb levels (European Best Practice Guidelines) increased from 49.4% at baseline to 80% after 12 months (p<0.001). Dialysis with VECM in stable chronic HD patients was associated with significantly improved Hb levels and lower rHuEpo requirements. These results suggest that the antioxidant properties of VECMs may impact favorably on anemia management in chronic HD patients. Possible mechanisms include enhanced membrane biocompatibility, reduced oxidative stress and inflammation with VECMs, resulting in improved red blood cell survival and/or rHuEpo responsiveness. This therapy may potentially contribute to more effective anemia management in hemodialysis patients, and merits further rigorous study.

225: Effect of Glycemic Control on Erythropoiesis Stimulating Agent Requirement in Diabetic Maintenance Hemodialysis Patients

EFFECT OF GLYCEMIC CONTROL ON ERYTHROPOIESIS STIMULATING AGENT REQUIREMENT IN DIABETIC MAINTENANCE HEMODIALYSIS PATIENTS Lon Sadowsky, S. Subramanian, D. Chewaproug, S. Aure, I. Dissanayake, R. Raja Albert Einstein Medical CenterPhiladelphia, Pennsylvania Anemia management is an important aspect of maintenance hemodialysis (MHD) therapy. It has been reported that diabetics have lower serum erythropoietin concentration than non-diabetics while maintaining similar hemoglobin levels. This may be to an effect of angiotensin II on erythropoiesis. Diabetic associated hyperglycemia reflected as high hemoglobin A1c (HbA1c), has been found to increase angiotensin II production. A large study has reported lower recombinant human erythropoietin (rHuEpo) requirement in diabetic MHD patients. To our knowledge there is no data on the influence of glycemic control on rHu-Epo requirements. This study was performed to determine if glycemic control affected rHu-Epo requirement in diabetic MHD patients. A retrospective analysis of MHD patients from two large urban hemodialysis units was performed. Patients were included if they carried the diagnosis of diabetes and on MHD for over 3 months. Exclusion criteria included active infection, evidence of active blood loss, and recent hospitalization within the month prior to data collection. Patients were divided into two groups, low (<6.5%) and high (≥ 6.5%) HbA1c. Data from a total of 149 patients were analyzed, and of them 92 diabetic patients included. We found patients with HgA1c of < 6.5% (n=49) required a significantly higher dose of rHuEpo when compared to those in the elevated HbA1c group (11,553 ± 10,306 units/HD vs. 6,147 ± 7585 units/ HD, p= 0.006) to maintain the same level of hemoglobin. There was no statistical difference in markers of iron adequacy and inflammation. There was a significant negative correlation of HbA1c with rHu-Epo dose (-0.289, p=0.006). These data suggest that glycemic control may play a role in rHu-Epo responsiveness. There was a decreased rHu-Epo requirement in diabetic patients with high HbA1c levels. This counterintuitive response may reflect an effect of hyperglycemia through angiotensin II mediated erythropoiesis. The clinical significance and mechanism of these findings need to be further elucidated.

Influence of Oxidative Stress and Inflammation on rHuEPO Requirements of Hemodialysis Patients With CRP Values “in Normal Range”

Aims We sought to evaluate influences of oxidative stress (OS) on rHuEPO requirements in hemodialysis patients without chronic inflammation. Methods Sixty-eight hemodialysis patients and 46 healthy controls underwent measurements plasma levels of antioxidative agents, such as glutathione peroxidase (GPX), superoxide dismutase (SOD), and oxidative compounds including malonyldialdehyde (MDA). We retrospectively analyzed the last 3 months’ rHuEPO requirements, iron indices, and CRP levels. Results Plasma levels for SOD, GPX, and MDA were 974.4 ± 216.4 U/gHb, 44.4 ± 13.6 U/gHb, 10.0 ± 2.0 nmol/mL, respectively yielding results that were different from healthy controls ( P < .0001). Increased OS negatively correlated with hemoglobin levels ( P < .0001) and positively correlated with rHuEPO requirements ( P < .01). Increased antioxidative capacity positively correlated with hemoglobin levels ( P < .0001) and negatively correlated with rHuEPO requirements ( P < .0001). For further analyses, hemodialysis patients were subgrouped according to rHuEPO requirements as group I (lowest 1/3, n = 23), group II (moderate 1/3, n = 23) and group III (highest 1/3, n = 22). Group III displayed the highest MDA ( P < .05), the lowest SOD ( P < .0001), and comparable GPX ( P < .05) levels. Group III also had the highest CRP and the lowest albumin levels compared with the others ( P < .01). Conclusion OS has strong adverse influences on rHuEPO responses of HD patients with “normal” CRP levels, but it should not be forgotten that CRP levels in the “normal” range may still reflect ongoing microinflammation.

Effect of protein-energy malnutrition on erythropoietin requirement in maintenance hemodialysis patients

Possible interactions between inflammatory and nutritional markers and their impact on recombinant human erythropoietin (rHuEPO) hyporesponsiveness are not well understood. We investigated the role of nutritional status in rHuEPO requirement in maintenance hemodialysis (MHD) patients without evidence of inflammation. This cross-sectional study included 88 MHD patients. The associations between required rHuEPO dose and malnutrition-inflammation score (MIS) and several laboratory values known to be related to nutrition and/or inflammation were analyzed. Anthropometric measures including body mass index, triceps skinfold thickness, and midarm circumferences were also measured. Twenty-three patients with serum C-reactive protein levels >10 mg/L were excluded from the analysis. The remaining 65 patients (male/female, 41/24; age 49.1+/-11.4 years; dialysis duration 99.7+/-63.0 months) were studied. These patients had moderate malnutrition and the average MIS was 7.4 (range 3-17). The average weekly dose of administered rHuEPO was 69.1+/-63.1 U/kg. Malnutrition-inflammation score had a positive correlation with the serum concentration of tumor necrosis factor-alpha, whereas it had a negative correlation with anthropometric measures, total iron-binding capacity, prealbumin, phosphorus, creatinine, and triglyceride. According to Pearson's correlation analysis, significant relationships of increased MIS with increased required rHuEPO dose and rHuEPO responsiveness index (EPO divided by hematocrit) were observed (p=0.008, r=-0.326; p=0.017, r=-0.306, respectively). Recombinant human erythropoietin dose requirement is correlated with MIS and adverse nutritional status in MHD patients without evidence of inflammation. Further research should focus on reversing the undergoing microinflammation for a better outcome in dialysis patients.

Possible Influence of Vitamin D Receptor Gene Polymorphisms on Recombinant Human Erythropoietin Requirements in Dialysis Patients

Background Vitamin D receptor (VDR) gene polymorphisms have been widely studied, especially to analyze their effects on calcium-phosphorus metabolism and secondary hyperparathyroidism in patients on dialysis. In this study, we sought to investigate the possible effects of these polymorphisms on the anemia of renal failure and recombinant human erythropoietin (rHuEPO) responses among patients receiving hemodialysis. Methods One hundred twenty-eight patients (52 females/76 males) underwent genotyping for the insertion/deletion Bsml (B→b, restriction site, exon VIII→IX) and Tagl (T→t, 352 exon IX) VDR gene polymorphisms. The mean value of the last 6 months’ monthly evaluated laboratory values (C-reactive protein, hemoglobin, iron indices, PTH, and albumin) and clinical findings (rHuEPO requirement, cumulative iron supplementation doses, and body weight) were analyzed retrospectively excluding patients with chronic inflammation, hemolytic anemia, or active blood loss such as gastrointestinal bleeding. Results Mean age and dialysis durations were 41.5 ± 11.8 years and 91.8 ± 45.3 months, respectively. Polymorphism percentages were as follows: Bsml; BB/Bb/bb: 32.2/63.6/4.2 and Tagl; TT/Tt/tt: 40.5/55.4/4.1%, respectively. BB variant of Bsml gene was related to lower rHuEPO needs ( P < .05) and also higher hemoglobin levels ( P < .005) when compared with the Bb/bb variant. Considering Tagl variants, transferrin saturation levels were lower ( P < .03) among patients with the Tt/tt variant, but there was no other significant difference in the mean values of other data between TT and Tt/tt variants. Conclusion The BB variant of Bsml was related to decreased rHuEPO requirements to achieve higher hemoglobin levels among maintenance hemodialysis patients without chronic inflammation.

Additional Effect of Hyperparathyroidism on Inflammatory Status and rHuEPO Requirements in Hemodialysis Patients

Background The aim of this study was to analyze the effects of elevated parathyroid hormone (iPTH) and C-reactive protein (CRP) on rHuEPO requirements and associated clinical and biochemical parameters of hemodialysis patients. Methods A total of 127 hemodialysis patients were included. Laboratory values from the previous 3 months (monthly measured CRP, iPTH, albumin, prealbumin, calcium, phosphorus, and hemoglobin) and clinical findings (rHuEPO requirements, iron supplements, Kt/V) were recorded retrospectively. Patients were subgrouped according to presence of hyperparathyroidism (mean iPTH > 350 pg/mL) and chronic inflammation (mean CRP > 8.5 mg/L) as group I (low iPTH, low CRP, n = 32), group II (high iPTH, low CRP, n = 32), group III (low iPTH, high CRP, n = 32), and group IV (high iPTH, high CRP, n = 31). Results We found that group IV had lowest hemoglobin ( P < .0001, .0001, .01, respectively), albumin ( P < .0001), prealbumin ( P < .0001, .0001, .02, respectively), and highest rHuEPO requirements ( P < .0001, .0001, .01, respectively) compared to other groups despite of similar iron indices. Group III also had lower albumin ( P < .002, .0001, respectively), prealbumin ( P < .001, .01, respectively), hemoglobin ( P < .001, .005, respectively), but higher rHuEPO requirements ( P < .01) compared to group I and group II. Conclusions We propose that hyperparathyroidism increases rHuEPO requirements and aggravates the negative effects of chronic inflammation in hemodialysis patients.

UNRESOLVED ISSUES IN DIALYSIS: Managing Erythropoietin Hyporesponsiveness

ABSTRACTThe anemia of chronic kidney disease is associated with cardiovascular disease, decreased quality of life, and mortality. The introduction of recombinant human erythropoietin (rHuEPO) has transformed the management of this condition. However, a significant proportion of patients fail to respond to even high doses of rHuEPO. Several factors have been implicated in the hyporesponsiveness to rHuEPO. Iron deficiency, whether absolute or functional, is considered the most important, and maintenance of adequate iron stores reduces rHuEPO requirements among patients on hemodialysis. However, traditional indices of iron that are currently utilized may not reflect iron stores accurately, and there is also increasing concern regarding the potential long‐term toxicity of parenteral iron therapy. Infection and inflammation also influence the response to rHuEPO, both by disruption of iron metabolism and by eliciting the release of cytokines that inhibit erythropoiesis. Oxidative stress may contribute to rHuEPO hyporesponsiveness directly by promoting lipid peroxidation in cell membranes, leading to increased erythrocyte fragility and reduced life span and also through its strong association with inflammation. Severe hyperparathyroidism can lead to a reduced number of erythroid progenitor cells. Inadequate dialysis dose, aluminum overload, nutritional factors such as deficiencies of carnitine, vitamin B12, folic acid, and vitamin C can also reduce the efficacy of rHuEPO therapy. Hyporesponsiveness to rHuEPO presents a challenge to both diagnosis and management in an era where optimizing response to rHuEPO is critical both in limiting the burgeoning costs of anemia management and improving clinical outcomes in the dialysis population.

Transdermal Androgen Therapy to Augment EPO in the Treatment of Anemia of Chronic Renal Disease

Hypogonadism and anemia are common comorbid conditions in dialysis patients. Testosterone replacement may improve such clinical parameters as anemia, sarcopenia, and low libido. Additionally, by increasing hemoglobin levels, testosterone replacement may allow for a dose reduction in recombinant human erythropoietin (rHuEPO), thereby reducing cost. This phase IV, single-center, placebo-controlled, double-blind study assessed the effect of transdermal testosterone on serum testosterone levels, rHuEPO dose required to maintain hemoglobin level, bone mineral content, lean body mass and fat content, cholesterol level, sexual function, and mood. Forty hypogonadal male hemodialysis patients who were administered rHuEPO were randomly assigned to 100 mg of topical 1% testosterone gel (Testim; Auxilium Pharmaceuticals, Norristown, PA) or placebo, applied daily for 6 months. Forty men with a mean age of 56 years and baseline serum testosterone level less than 300 ng/dL (< 10.4 nmol/L) participated in this trial. In men assigned to administration of transdermal testosterone, there was an increase beyond that in the placebo group in mean serum testosterone (77.1 ng/dL [2.7 nmol/L]), dihydrotestosterone (DHT; 0.8 nmol/L), and estradiol levels (6.3 pg/mL [23.0 pmol/L]) and a decrease in mean serum luteinizing hormone levels (-3.1 IU/L). Compared with subjects administered placebo, participants on testosterone replacement therapy did not show an appreciable change in rHuEPO dose (mean difference adjusted for baseline values, 12.6 U/kg/wk; P = 0.73), bone mineral density, lean body mass or fat content, cholesterol level, sexual function, or mood. Daily administration of 100 mg of topical 1% testosterone gel for 6 months failed to significantly increase serum testosterone or DHT levels in hypogonadal men with end-stage renal disease. Treatment with transdermal testosterone did not impact on rHuEPO requirement or clinical parameters in this small placebo-controlled study. Greater serum testosterone levels may be required to show clinical benefit in men with end-stage renal disease.

The Effect of Proinflammatory Cytokine Gene and Angiotensin-Converting Enzyme Polymorphisms on Erythropoietin Requirements in Patients on Continuous Ambulatory Peritoneal Dialysis

The correction of anemia by recombinant human erythropoietin (rHuEPO) improves quality of life and prolongs life in end-stage renal failure. rHuEPO requirements for an individual are determined by a range of factors, including iron deficiency and inflammation. Single nucleotide polymorphisms in the promoter sequence of several proinflammatory cytokines have been shown, in different fields of medicine, to influence the cytokine response to different stimuli, with effects on clinical outcome. The angiotensin-converting enzyme (ACE) insertion/deletion polymorphism and polymorphisms in the promoter regions of the genes for tumor necrosis factor alpha (-308 A/G), interleukin-6 (-174 G/C), and interferon gamma were examined for their association with rHuEPO requirements in 112 patients on continuous ambulatory peritoneal dialysis (CAPD). Genomic DNA was extracted from peripheral blood leukocytes and genotyping performed with ARMS-PCR methodology, with sequence-specific primers. We examined rHuEPO requirements and C-reactive protein at baseline and during a 6-month study period. We found no significant effect of proinflammatory cytokine polymorphisms on rHuEPO responsiveness. However, throughout the study, we observed that there was a significantly higher rHuEPO requirement in the II and ID ACE genotypes compared with the DD group, which remained an independent association following multivariate analysis. ACE insertion/deletion polymorphism may determine rHuEPO responsiveness in CAPD patients and should be considered in relative rHuEPO resistance.

The effect of hemodialysis duration on 703 hemodialysis patients in our center

There are limited data on demographics, long‐term follow‐up, and iron/rHuEPO requirements of hemodialysis (HD) patients in Turkey. The aim of the study was to analyze the effects of the HD duration, primary illness, blood pressure, and age on serum albumin, CRP, blood pressure, iron/rHuEPO requirements, PTH, and HCV positivity of HD patients. 703 patients (280 women, 423 men, aged 47.8 ± 15.5 years) from 4 HD units were included and grouped according to the duration on HD. The demographic, clinical, and biochemical data of the last 3 months for each patient were recorded retrospectively. When the groups were compared, patients with a longer HD duration were younger and percentage of diabetic patients decreased as the duration increased. Serum albumin and CRP levels were similar between the groups. When the groups were compared according to the blood pressure profiles, after the 5th year, a decline in the systolic blood pressures was observed. Diastolic blood pressures were similar across the years. There was no significant difference in need of antihypertensive medicines. Iron requirements showed a fall after the 5th year, and an increase in after the 10th year. There was a decline in the hematocrit levels by the duration on HD but there was no change in rHuEPO requirements over the years. Parathyroid hormone levels and HCV positivity tended to increase across the years. Our results revealed that during the first 10 years, age, etiology (diabetes, hypertension), and blood pressure control seemed to be important factors affecting survival. Whereas, after the 10th year, patients seemed to be more prone to the long‐term complications of HD, such as HCV infection, anemia, secondary hyperparathyroidism.