clinical pharmacology and translational medicine...2clinical pharmacology group, health research...

Anxo Fernández-Ferreiro1,2, Mara Lisbet Cabana-Carcasi3, Rafael Alonso-Valente3, Eduardo Echarri-Arrieta1,2, Sara Blanco-Dorado1,2, Andrea Luaces-Rodriguez2, Antón Fernández-Ferreiro4, Miguel González-Barcia1,2, María J Lamas1,2*

1Pharmacy Department, Xerencia de Xestión Integrada de Santiago de Compostela. Spain (SERGAS).2Clinical Pharmacology Group, Health Research Institute of Santiago de Compostela. Spain (IDIS-ISCIII). 3Nephrology Department, Xerencia de Xestión Integrada de Santiago de Compostela. Spain (SERGAS).4Clinical Analysis Department. Hospital Universitario Nuestra Señora de la Candelaria. Tenerife. Spain. (SCS).

Abstract Background: The erythropoiesis-stimulating agents (ESAs) are commonly used in the management of anemia in patients with chronic kidney disease.

Objective: The aim of this study is to identify the parameters that make it necessary to use ESAs in patients with chronic kidney disease in peritoneal dialysis program.

Methods: A cross-sectional study of patients on peritoneal dialysis during one year was performed, analyzing the factors associated with the use of ESAs and its resistance.

Results: 77.4% of the patients included in the study (n=53) were treated with erythropoiesis-stimulating agents. It has been observed that the main factors that trigger the administration of ESAs area prolonged time on peritoneal dialysis (29.96 months vs. 16.67 months), a decreased residual renal function (3.76 vs 18.17 ml/min) and a deficient nutritional status (albumin: 3.77 g/dl vs. 4.14 g/dl, prealbumin: 39.58 mg/dl vs 46.73 mg/dl), presenting statistically significant differences (p <0.005) in all the parameters indicated.

Conclusions: Maintaining a residual renal function and a good nutritional status are key factors that avoid the use of ESAs.

Factors Contributing to use of Erythropoiesis Stimulating Agents in Patients with Chronic Kidney Disease in Peritoneal Dialysis Program: a Cross-Sectional Study.

Research Article

Clinical Pharmacology and Translational Medicine © All rights are reserved by Maria J Lamas, et al.

Introduction

Treatment of symptomatic anemia associated with chronic kid-ney disease (CKD) is one of the indications of erythropoiesis-stimul-ating agents. Several studies have shown a satisfactory clinical respo-nse to the treatment with ESAs, since 90% of the patients achieved the objectives of the treatment [1]. These studies also indicate that ESAs have the same effectiveness in hemodialysis, continuous ambulatory peritoneal dialysis and patients in predialysis with chronic kidney disease [2].

Relative resistance to the effect of ESAs is a common problem in managing the anemia of patients with CKD [3]. ESA hyporesponsive-ness has been found to be associated with an increase in morbidity

and mortality of patients on hemodialysis and peritoneal dialysis [4, 5]. It has been suggested that erythropoietin treatment itself can cause inflammation and high doses are associated with increased mortality. Therefore, the detection, treatment and management of resistance seem to be a better therapeutic option than simply increasing the dose [6].

There are different causes of resistance, which are interrelated. It has been shown that inflammatory conditions characterized by elevated tumor necrosis factor alpha (TNF-), interleukin 1 (IL-1), interleukin 6 (IL-6) and interferon gamma (IFN-γ) and others are related to an inadequate response to therapy [7, 8]. Inflammatory processes often trigger iron deficiency because the iron cannot be mobilized from the storage locations in the reticuloendothelial system. It is inhibited by both the proliferation and differentiation of erythroid progenitor cells, and thus the response to erythropoietin [9]. Ferritin values below 100 mg/dl and ferritin saturation <20% is one of the most frequent causes of ESAs resistance. Malnutrition is usually another trigger of resistance, the association between inflammation, malnutrition and anemia syndrome has been coined malnutrition-inflammation complex (MICS) [10, 11] and it is typically identified by concurrent elevations in inflammation markers and decreases in nutr-

ISSN:2572-7656

*Address for Correspondence: Maria Jesus Lamas, PharmD, Pharmacy Department, Hospital Clinico Universitario de Santiago de Compostela. Calle A Choupana s/n Santiago c.p.15701 (Spain), Tel: + 34 981950918; E-mail: maria.jesus.lamas.dí[email protected]

Received: March 22, 2017; Accepted: May 03, 2017; Published: May 05, 2017

Clin Pharmacol Transl Med, 2017 Volume 1(2): 38-43

Applis

Highlight

ional nutritional markers such as albumin and cholesterol. The increased severity of MICS is associated with higher ESAs requirem-ents and between 35% and 65% of dialysis patients suffer from this syndrome [12]. Thus, a decreased Body Mass Index (BMI) and/or a decreased level of cholesterol are associated with a poor control of anemia in patients on hemodialysis [13]. Other causes of resistance to erythropoietin is hyperparathyroidism, existing an inverse relationship between the level of PTH and the response to rHuEpo [4]. It has also been shown that the use of inhibitors of angiotensin converting enzyme (ACE) and angiotension receptor blockers (ARBs) promote hyporesponsiveness to ESAs [15, 16]. On the other hand, a good cleansing technique is associated with a better response to ESAs as well as with the persistence of some degree of renal function, both due to its purifying aspects [17, 18].

These factors also affect the endogenous erythropoietin response. For this reason, it is necessary to investigate the possible causes of resistance in order to avoid them and therefore be able to delay or avoid the use of ESAs [19].

MethodsOverview and Patient Selection

This cross-sectional study comprised 53 patients undergoing peritoneal dialysis in a third level hospital during the period of one year. The study included patients who have been a minimum of ten months on peritoneal dialysis. Exclusion criteria were: active infection, tumor processes, surgical and/or transfusions within less than 3 months at the time of data collection. Patients receiving immunosup-pressive or cytotoxic medication that could cause anemia were also excluded. Sample collection was undertaken with informed consent and ethical review board approval of the corresponding institution, in accordance with the tenets of the Declaration of Helsinki.

The main objective of the study is to identify the parameters that make it necessary the use of ESAs in patients with chronic kidney disease on peritoneal dialysis program.

Data Collection General characteristics of the population: age; sex; presence or absence of diabetes and/or hypertension; etiology of chronic renal failure; time on peritoneal dialysis program; dialysis dose; using or not using drugs like ACE inhibitors, ARBs or aliskiren, phosphorus binders containing aluminum in the composition; and finally handling of iron deficiency with administration of oral and intravenous iron.

Characteristics of dialysis Creatinine clearance weekly (Clcrw), Creatinina clearance weekly (Clcrw) and Urea clearance rate (Kt/V).

Nutritional variables As analytical indicators of malnutrition: decreased plasma protein concentrations and total protein in different fractions (albumin, prealbumin, retinol carrier protein (RBP) and transferrin). As supplementary measures of nutritional status: absolute lymphocyte count, serum creatinine, total cholesterol, HDL cholesterol, total triglycerides, plasma bicarbonate and vitamin status (vitamin B12 and Folic Acid). Moreover, we have collected if the patients received or not nutritional supplements and anthropometric parameters such as Body mass index (BMI).

Inflammatory variablesC-reactive protein high sensitivity (PCRus), interleukin-6 (IL6),

tumor necrosis factor alpha (TNF α), homocysteine and beta 2 microglobulin (β2mcg). Blood samples for determination of inflamm-atory parameters were obtained in the morning after at least 12 hrs fasting. They were kept refrigerated or frozen at –20 °C until process-ing, which was carried out by the chemiluminescence technique.

The degree of hyperparathyroidism was evaluated by the value of of intact parathyroid hormone (iPTH).

Hematological parameters Hemoglobin (Hb), hematocrit (Ht), mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH). Values of iron, ferritin and transferrin saturation were also collected.

In order to detect possible cardiovascular consequences related to the use of ESAs, we have collected the values of systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR).

Statistical Analysis

The statistical analysis was performed using the IBM® SPSS vers-ion 20.

Qualitative variables were expressed as a percentage. For quantit-ative variables, we have used the mean, standard deviation, median and interquartile range. For the comparison of both groups, the mean, 95% confidence interval for the mean, median and interquartile range were used. We have used the Pearson chi square and Fischer F contrasts in the qualitative parameters. For quantitative parameters, we used the nonparametric Mann-Whitney U due to the small sample size. Statistical significance was set at p <0.005.

Results

Table 1 shows the results obtained from the 53 patients included in the study, 41 were treated with ESAs compared to 12 patients untre-ated. Peritoneal dialysis was performed with dialytic compatibles and isotonic solutions in all the patients, not using in any case phosphorus bindersw aluminum in its composition. Statistically significant differe-nces between both groups were found in the peritoneal dialysis time, being higher in the group treated with ESAs, with a mean time of 29.96 months compared to 16.67 months in the group untreated. The quality of dialysis was better in the untreated group than in the treated group with ESAs, the former having a mean creatinine clearance weekly of 113.55 L/S compared to 76.26 L/S. The residual renal function was significantly more maintain in the group of patients not treated with ESAs, presenting a mean value of 18.17 mL/min/1.73 m2, compared to the 3.76 mL/min/1.73 m2 of the treated group. We have also found significant differences in the use of exogenous iron, observing that in patients receiving ESAs and requiring iron administration, the intravenous route was chosen in most cases.

Table 2 Shows the nutritional values obtained. Statistically signifi-cant differences were obtained in the values of albumin and pre album-in between both groups, obtaining higher values of both parameters in the untreated group, indicating a better nutritional status. The albumin mean values were 4.14 g/dl for the untreated group versus 3.77 g/dL in the group treated with ESAs. Prealbumin was also higher in the untrea-ted group, 46.73 mg/dl versus 39.58 mg/dl in the treated group. Trigly-cerides reached high levels, showing statistically significant differences between both groups, presenting levels of 165.45 mg/dl in the group


"Fernández Ferreiro A, Cabana Carcasi ML, Alonso Valente R, Echarri Arrietaa E, Blanco Dorado S, Fernández Ferreiro A,Gonzalez BArcia M, , Lamas MJ. Factors Contributing to use of Erythropoiesis Stimulating Agents in Patients with Chronic Kidney Disease in Peritoneal Dialysis Program: a Cross-Sectional Study.Clin Pharmacol Transl Med. 2017; 1(2): 38-43."

Citation: Swerdlow RH, Lyons KE, Khosla SK, Nashatizadeh M, Pahwa R. A Pilot Study of Oxaloacetate 100 mg Capsules in Parkinson ’sdisease Patients. J Parkinsons Dis Alzheimer Dis. 2016;3(2): 4.

*Address for Correspondence:Leandro Bueno Bergantin,Rua Pedro de Toledo, 669 – Vila Clementino, São Paulo– SP, Brazil, CEP: 04039-032. Fax: 1-913-588-0681;E-mail: [email protected]

UNTREATED PATIENTS (n=12)

TREATED PATIENTS (n=41) P VALUE

Age 44.64 (34.50 -- 54.77) 1 52.21 (46.84 -- 57.58)1 0.126 46.0 (31.00--56.00) 2 51.00 (42.5 -- 64.00) 2

Diabetes 16.7% (n=2) 26.8% (n=11) 0.707 High blood pressure 91.7% (n=11) 80.5% (n=33) 0.665

Genre(esto ya se había corregido)

Men 58.3% (n=7) 56.1% (n=23) 1 Women 41.7% (n=5) 43.9% (n=18)

Time on peritoneal dialysis (months) 16.67 (11.72--21.63) 1 29.96 (22.91 -- 37.02) 1 0.038 13.47 (10.20 --23.10) 2 21.17 (14.46 -- 39.06) 2

Urea clearance rate (Kt/V) 2.48 (2.10--2.80) 1 2.03 (1.98--2.18) 1 0.076 2.37 (1.90-2.16) 2 1.97 (1.85 -- 2.17) 2

Creatinina clearance weekly (Clcrw) 113.55 (85.75--141.35) 1 76.26 (64.14--88.39) 1 0.007 92.00 (82.70-- 163.0) 2 69.10 (47.80--87.67) 2

Residual Renal Function (RRF) 18.17 (-1.85 --- 38.19) 1 3.76 (2.49 -- 5.04) 1 7.83 (6.60 -- 14) 2 2.75 (0.49 -- 6.13) 2 0.001

Treated with ACE/ARBs 66.7% (n=8) 43.9% (n=18) 0.202

% Treated with iron

No 16.7% (n=2) 43.9% (n=18)

Oral 41.7% (n=5) 2.4% (n=1) 0.001 Intravenous 41.7% (n=5) 53.7% (n=22)

1 Mean (95% confidence interval. Lower limit -- Upper limit); 2 Median (interquartile range)

Table 2. Nutritional values of the population in the study



BMI 28.84 (25.27--32.41) 1 25.77 (24.38--27.17) 1

0.151 27.42 (25.03--33.83) 2 25.37 (22.70--28.74) 2

Albumin 4.14 (3.84--4.4491 3.77 (3.63--3.92) 1

0.026 4.200 (3.80--4.60) 2 3.75 (3.47- 4.10) 2

Prealbumin 46.73 (41.42--52.03) 1 39.58 (36.70--42.46) 1

0.019 3.75 (41.00--53.00) 2 40.0 (34.00--47.25) 2

RPB 12.89 (10.92--14.85) 1 13.41 (12.30--14.52) 1

0.871 13.400 (10.10--15.20) 13.50 (10.65--13.50) 2

Transferrin 204.64 (176.21--233.07) 1 187.00 (177.49--196.51) 1

0.366 204.00 (161.00--257.00) 2 186.50 (171.75--204.25) 2

Lymphocytes 1.37 (0.99 -- 1.75) 1 1.60 (1.35 --1.85) 1

0.595 1.32 (0.76 -- 1.78) 2 1.39 (1.03 -- 2.29) 2

Creatinine 6.53 (5.31--7.75) 1 9.02 (8.01--10.04) 1

0.040 6.40 (5.00--7.50) 2 8.55 (6.90--11.15) 2

Cholesterol 178.91 (141.28--216.54) 1 167.87 (155.87--179.87) 1

0.848 166.00 (146.00- 256.00) 2 159.50 (144.25--195.75) 2

Cholesterol HDL 36.64 (27.87—45.41) 1 37.61 (32.66—42.55) 1

0.778 33.0 (28.00—39.00) 2 35.50 (27.50 – 46.50) 2

Triglycerides 165.45 (122.57--208.34) 1 127.21 (109.18--145.24) 1

0.041 151.00 (117.00--210.00) 2 116.50 (93.50--116.50) 2

Oral bicarbonate 24.67 (22.59--26.75) 1 26.81 (25.83--27.80) 1

0.058 23.70 (24.77--28.92) 2 26.55 (24.77 – 28.92) 2

Folic Acid 5.51 (3.55--7.47) 1 32.90 (10.43 -- 55.40) 1

0.983 4.70 (3.80-6.60) 2 4.45 (3.05 -- 40.10) 2

B12 Vitamin 552.91 (410.23 -- 695.59) 1 570.26 (493.30--647.23) 1

0.474 511.00 (447.00--617.00) 2 510.50 (359.25--702.75) 2

Patients with nutritional supplements

8.3% (n=1) 12.2% (n=5) 1

1 Mean (95% confidence interval. Lower limit -- Upper limit); 2 Median (interquartile range)



not treated with ESAs versus 127.21 mg/dl. Serum creatinine achieved higher values in the group treated with ESAs, showing statistically significant differences with the other group.

Table 1. Main characteristics of the population in the study

Vitamin status of the patients was at optimum values in order to avoid a decrease in hemoglobin synthesis for the lack of these factors. Sodium bicarbonate presented values greater than 22 mmol/L, thus indicating no acidemia, which is usually associated with protein degradation and hypoalbuminemia. Other parameters where no statistically significant differences but higher levels in the untreated group ESAs were found are transferrin, cholesterol and BMI.

High-grade inflammation was found in both groups, as it can be seen in Table 3 where all the parameters presented values above the normal ones. The values are higher in the group of patients treated with ESAs. The only parameter that showed statistically significant differences was beta 2 microglobulin, presenting a mean value of 32.16 mg/L in the treated group compared to 16.85 mg/L in the other group.

Regarding the status of the parathyroid, no significant differenc-es between groups were found, both groups had hyperparathyroidism,

slightly higher in the untreated group, with mean values of iPTH 309.45 versus 274.00 in the treated group.

Table 4 shows the results obtained in regards to blood parameters and iron metabolism. No statistically significant differences on any of the studied parameters were found. The hemoglobin and hematocrit values were relatively low in the group treated with ESAs, unlike the MCV, MCH, ferritin and transferrin saturation that showed higher values. Normal erythropoiesis requires, among other things, an adequate iron availability necessary for the synthesis of Hb. The iron metabolism studied by the parameters shown above was more increased in the treated patients, although both groups showed good values of iron, ferritin and transferrin saturation.

Regarding the cardiovascular parameters, the patients showed above normal mean values of blood pressure in both groups without significant differences between the groups.

Table 3. Inflammatory parameters of the population in the study



PCRus 0.790 (0.03 -- 1.62) 1 0.83 (0.44 -- 1.23) 1 0.833

0.28 (0.16 -- 0.900) 2 0.64 (0.14 --0.64) 2

IL6 6.200 (0.36 --12.03) 1 10.87 (7.090 --14.66) 1

0.101 3.00 (2.00 -- 5.80) 2 7.400 (3.27--11.87) 2

TNFα 16.11 (13.16 -- 19.06) 1 20.24 (17.93--22.55) 1

0.065 15.20 (14.10 -- 21.10) 2 18.55 (15.67 -- 21.10) 2

Homocysteine 22.36 (16.71--28.02) 1 24.16 (19.73--28.58) 1

0.946 20.00 (15.00--31.00) 2 22.0 (16.00--29.25) 2

B2M 16.85 (13.94--19.75) 1 32.16 (26.30--38.02) 1

0.012 17.80 (12.00--15.20) 2 27.35 (17.95--47.300) 2

1 Mean (95% confidence interval. Lower limit -- Upper limit) 2 Median (interquartile range)

Table 4. Blood parameters of the population in the study



Hemoglobin 12.05 (11.23--12.87) 1 11.48 (11.08--11.89) 1

0.191 11.80 (11.20--13.20) 2 11.55 (10.75--12.17) 2

Hematocrit 36.13 (33.83-- 38.43) 1 34.64 (33.33--35.96) 1

0.195 36.50 (30.90--98.80) 2 34.60 (31.85--37.35) 21

MCV 90.03 (86.59--93.47) 1 92.02 (90.08--93.96) 1

0.264 89.30 (88.0--91.20) 2 91.25 (88.95--95.62) 2

MCH 29.93 (29.29--30.57) 1 30.57 (29.94--31.21) 1

0.339 29.70 (29.30--30.40) 2 30.50 (29.200--31.72) 2

Iron 84.09 (64.29--103.89) 1 92.76 (80.57--104.95) 1

0.915 86.00 (68.00--101.00) 2 87.00 (69.50--104.00) 2

Ferritin 471.18 (115.90--826.46) 1 624 (463--784.94) 1

0.093 269.00 (208.00--636.00) 2 593.50 (295.00--736.00) 2

Transferrin Saturation 29.89 (23.07--36.71) 1 35.66 (30.93 -- 40.39) 1

0.510 31.07 (21.23--39.89) 2 33.12 (26.70--95.62) 2

1 Mean (95% confidence interval. Lower limit -- Upper limit) 2 Median (interquartile range)



https://www.ncbi.nlm.nih.gov/pubmed/26613895

Discussion In our study the variables related to the use of ESAs in patients

with peritoneal dialysis were identified: residual renal function, quality of dialysis, duration of the dialysis and nutritional status.

As other studies have previously shown, we observed that the time on peritoneal dialysis is an essential factor in the necessity of receiving or not receiving ESAs [20]. As the residual renal function was more maintained, less exogenous erythropoietin was required. This is because endocrine function in the kidney is maintained and therefore the endogenous erythropoietin synthesizing function. Therefore, it is very important to preserve as much as possible the patient's renal function [21]. Regarding nutritional status, we obser-ved that patients no treated with ESAs have a better nutritional status, as well as serum albumin, prealbumin and triglycerides levels, in accordance with other authors [22]. Creatinine, which is an indicator of static protein reserves, lacks of interest because, in this case, represents the accumulation of substances not eliminated by the kidneys and not the protein reserves. The concentration of bicarbon-ate is a useful parameter in patients with GFR <60 ml/min, where values below 22 mmol/l indicate a state of acidemia associated with protein degradation and hypoalbuminemia [23]. In our patients, both groups are above that value, thus not interfering in previously reported values.

Hypoalbuminemia is one of the most powerful predictors of morbidity and mortality in patients on dialysis [24]. Initially attributed to malnutrition, now it is known that its origin is multifactorial and may be related to nutritional factors, comorbid conditions and inflammation, hence the necessity of taking into account the inflammatory status of our patients [25].

The inflammatory condition was increased in both groups, showing all the parameters values above normal. Only beta 2 microglobulin of the studied parameters presented statistically significant differences between groups, having higher levels in the group of patients treated with ESAs, representing a risk factor for development of amyloidosis [26]. The interleukin 6 and tumor necrosis factor alpha were also higher in the treated group probably due to the administration of ESAs itself or a more frequently administration of intravenous iron in patients not treated [27]. There are studies that relate the malnutrition in peritoneal dialysis to the existence of status of chronic inflammation, explaining the associat-ion by the release of IL6 during dialysis that can cause anorexia, muscle breakdown and decreased hepatic synthesis of albumin. The studied inflammatory parameters presented high values, although they were lower than the ones observed in previous studies [28]. The reason may be that the erythropoietin administration was subcutan-eous in all patients, that optimal dialysis was performed in most of them and that folic acid supplements and vitamin B6 were administ-ered [18, 29].

The most important limitation of the study is its small sample size, although it should be noted that the population on peritoneal dialysis is less than performing hemodialysis. On the other hand, our study has the advantage of homogeneity, to belong to a single medical doctor and to be treated with the same therapeutic criteria. The classical resistance factors, such as inflammation, iron deficiency or malnutrition-inflammation complex, have been known almost from the beginning of the use of ESAs to treat anemia associated with CKD [30]. In recent years, new molecular and genetic mechanisms that

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2. Muirhead N. Factors Affecting the Response to Erythropoietin in Chronic Renal Failure. Semin Dial. 1991; 4:5-8. [Crossref]

3. Bamgbola O. Resistance to erythropoietin-stimulating agents: etiology, evaluation, and therapeutic considerations. Pediatr Nephrol. 2012; 27:195-205. [Crossref]

4. Besarab A and Yee J. Candidate biomarkers for erythropoietin response in end-stage renal disease. Kidney Int. 2011; 79:488-490. [Crossref]

5. Guerrero-Riscos MÁ, Montes-Delgado R, Seda-Guzmán M and Praena-Fernández JM. Erythropoietin resistance and survival in non-dialysis patients with stage 4-5 chronic kidney disease and heart disease. Nefrologia. 2012; 32:343-352. [Crossref]

6. Rainville N, Jachimowicz E and Wojchowski DM. Targeting EPO and EPO receptor pathways in anemia and dysregulated erythropoiesis. Expert Opin Ther Targets. 2016; 20:287-301. [Crossref]

7. Chait Y, Kalim S, Horowitz J, Hollot CV, Ankers ED, Germain MJ et al. The greatly misunderstood erythropoietin resistance index and the case for a new responsive-ness measure. Hemodial Int. 2016; 20:392-398. [Crossref]

8. López-Gómez JM, Pérez-Flores I, Jofré R, Carretero D, Rodríguez-Benitez P, Villav-erde M, et al. Presence of a Failed Kidney Transplant in Patients Who Are on Hemodialysis Is Associated with Chronic Inflammatory State and Erythropoietin Resistance. J Am Soc Nephrol. 2004; 15:2494-2501. [Crossref]

9. Kim A and Nemeth E. New insights into iron regulation and erythropoiesis. Curr Opin Hematol. 2015; 22:199-205. [Crossref]

10. Kalantar-Zadeh K, Ikizler TA, Block G, Avram MM and Kopple JD. Malnutrition-inflammation complex syndrome in dialysis patients: causes and consequences. Am J Kidney Dis. 2003; 42:864-881. [Crossref]

11. Rattanasompattikul M, Molnar MZ, Zaritsky JJ, Parta Hatamizadeh, Jennie Jing, Keith C. Norris, et al. Association of malnutrition-inflammation complex and respo-nsiveness to erythropoiesis-stimulating agents in long-term hemodialysis patients. Nephrol Dial Transplant. 2013; 28:1936–1945. [Crossref]

12. Kalantar-Zadeh K, McAllister CJ, Lehn RS, Lee GH, Nissenson AR and Kopple JD. Effect of malnutrition-inflammation complex syndrome on EPO hyporesponsi-veness in maintenance hemodialysis patients. Am J Kidney Dis. 2003; 42:761-773. [Crossref]

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16. Cole J, Ertoy D, Lin H, Roy L. Sutliff, Eric Ezan, Tham T. Guyene, et al. Lack of angiotensin II-facilitated erythropoiesis causes anemia in angiotensin-converting enzyme-deficient mice. J Clin Invest. 2000; 106:1391-1398. [Crossref]

account for the resistance to erythropoietin have been investigated, such as JACKSTAT signaling mechanism [31], ACE enzyme polymo-rphisms [32] and mutations in the gene responsible for the expression of HFE protein [33]. The application of this knowledge in the near future will help to clarify some of the questions in the management of patients under erythropoietin treatment. The knowledge of the ment-ioned erythropoietin resistance factors would allow us to optimize ESAs therapy by acting on modifiable factors.

AcknowledgementsA.F-F. acknowledge the support of Instituto de Salud Carlos III (RioHortega research grant CM15/00188)

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https://www.kidney.org/sites/default/files/docs/kdoqi2000nutritiongl.pdf



https://www.omicsonline.org/open-access/long-dialysis-time-is-the-more-important-factor-of-erythropoietin-response-in-hemodialysis-patients-with-diabetes-than-ktv-2161-0959.1000189.php?aid=36917









http://www.nejm.org/doi/full/10.1056/NEJMoa060900#t=article





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