An-Najah National University Faculty of Graduate Studies Evaluation of anemia management among hemodialysis patients in Palestine: associated factors and clinical outcomes By Nada Sadek Rajabi Supervisor Dr. Samah Al-Jabi This Thesis is Submitted in Partial Fulfillment of the Requirements for the Degree of Master of Clinical Pharmacy, Faculty of Graduate Studies, An-Najah National University, Nablus, Palestine. 2020 ii Evaluation of anemia management among hemodialysis patients in Palestine: associated factors and clinical outcomes By Nada Sadek Rajabi This Thesis was Defended Successfully on 23/1/2020 and approved by: Defense Committee Members Signature 1. Dr. Samah W. Al-Jabi / Supervisor .…….……..… 2. Dr. Hussein Hallak / External Examiner ...……………. 3. Dr. Rowa Al Ramahi / Internal Examiner …...…………. iii االهداء ، رمز حالمو فينا بكل ثبات وعزيموأالى الداعم الصامد الذي لم يتنازل ولم يتوارى يوما عن تحقيق أبي الغالي... التضحيو الذى افنى حياتو في ، الحضن الدافئ الى القمب الطيب الذي زرع الصدق واالخالص في قموبنا أمي الحبيبو ......... رعايتنا ومراه حياتي مشاركي ذكرياتي وعاىدي شبابيو وأيامي لتيروحي وأصدقاء طفو الى ...................... أخواتي حياتي... الحبيب خيأالى سندي ورفيقي ..... وصمودي حالميأالى صديقاتي ورفاق دربي وداعمي الى أساتذتي األفاضل الذين اضاؤوا بعمميم عقولنا روا جيدا في مساندتيالى زمالئي وزميالتي الذين ساندوني ولم يدخ الى كل من رافقني وكل من ساىم في تحقيق ىذا االنجاز iv الشكر والتقدير نعم عمي أالكثير و من خيرهعمي ن م حمدا كثيرا طيبا مباركا فيو أنالحمد والشكر هلل رب العالمين نفسو وزنة عرشو الحمدهلل عدد خمقو ورضى عانني عمى انجاز ىذا العمل. أمن فضمو في العمم و .ماتوومداد كم دكتوره سماح الجابي الرشادىا لي خالل دراستي المشرفتي اتقدم بخالص الشكر واالمتنان الى في دعميا لي.كانت دائما ودوده ومتفانيو ، العميا واعطائيا لي فرصة العمل عمى ىذا المشروع ضل في الصرح العممي الكبير في قسم فاكل االساتذه والمشرفين األويسرني ان أتقدم بجزيل الشكر ل في جامعو النجاح الوطنية. ةالصيدلو السريري بشكل عام لوزاره الصحة الفمسطينية ومستشفى النجاح الوطني الجامعي وأود ان أتوجو بالشكر لمساعدتي لموصول الى المعمومات الالزمو ليذا البحث.قسام غسيل الكمى بشكل خاص أو .عون وساىم في انجاز ىذا العمل لو مني كل الشكر والتقديرولكل من مد لي يد ال v االقرار ة التي تحمل العنوان:انا الموقع ادناه مقدم الرسال Evaluation of anemia management among hemodialysis patients in Palestine: associated factors and clinical outcomes باستثناء ما تمت اإلشارة إليو حيثما ،ت عميو الرسالة ىو من نتاج جيدي الخاصأقر بأن ما اشتمم ، وأن ىذه الرسالة ككل أو أي جزء منيا لم يقدم من قبل لنيل أي درجة أو لقب عممي أو بحثي ورد لدى أي مؤسسة تعميمية أو بحثية أخرى. Declaration The work provides in the thesis, unless otherwise referenced, is the researcher's own work, and has not been submitted elsewhere for any other degree or qualification. Student’s name: اسم الطالب Signature: التوقيع Date: خالتاري vi List of content No Contents Page Dedication Iii Acknowledgment Iv Declaration V List of tables Viii List of appendices Ix List of symbols and abbreviations X Abstract Xi Chapter One: Introduction 1 1.1 Background 1 1.1.1 Anemia in CKD 2 1.1.2 Symptoms and complications related to anemia in CKD 5 1.1.3 Diagnosis and evaluation of anemia in CKD 6 1.1.4 Treatment of anemia in CKD 8 1.2 Statement of problem 9 1.3 Research objectives 10 1.3.1 General objective 10 1.3.2 Specific objectives 10 1.4 Significance 11 1.5 Literature review 11 Chapter Two: Methodology 19 2.1 Study design and setting 19 2.2 Sample size 19 2.3 Data collection 20 2.3.1 Tools used in data collection 20 2.4 Inclusion and exclusion criteria 22 2.4.1 Inclusion criteria 22 2.4.2 Exclusion criteria 22 2.5 Statistical analysis 22 2.6 Ethical consideration 23 Chapter Three: Results 24 3.1 Demographic characteristics of the study sample 24 3.2 History of renal disease of the study sample 26 3.3 Herbal remedies used by the study sample 26 3.4 Comorbid disease among the study sample 28 3.5 Chronic medications used by the study sample 30 3.6 Hemoglobin level for the study sample 33 3.7 Iron status monitored for the study sample 34 3.8 Erythropoietin stimulating agent used in the study sample 35 vii 3.9 Some laboratory indices recorded for the study sample 35 3.10 Socio-demographic characteristics of the study sample with differences in hemoglobin goal 37 3.11 Disease related factors of the study sample with differences in hemoglobin goal 38 3.12 Health related quality of life of the study sample 40 3.13 Self-reported EQ-5D-5L health states and EQ-VAS 42 3.14 Correlation between EQ-5D-5L index and EQ-VAS 43 3.15 EQ-5D-5L index vs hemoglobin goal 43 Chapter Four: Discussion 45 Chapter Five: Conclusion 53 5.1 Strengths and limitations 53 5.2 Conclusion 54 5.3 Recommendations 54 References 56 Appendices 67 viii List of Tables No Tables pages Table 3.1 Demographic characteristics of the study sample 25 Table 3.2 History of renal disease of the study sample 26 Table 3.3 Herbal remedies use by the study sample 27 Table 3.4 Comorbid diseases among the study sample 28 Table 3.5 Total disease among the study sample 29 Table 3.6 Chronic medications used by the study sample 30 Table 3.7 Hemoglobin level of the study sample 33 Table 3.8 Iron status recorded for the study sample 34 Table 3.9 Hemoglobin level and Darbepoetin administration in the study sample 35 Table 3.10 Some laboratory indices recorded for the study sample 36 Table 3.11 Demographic characteristics of patient sample vs hemoglobin goal 37 Table 3.12 Disease related factors associated vs hemoglobin goal 39 Table 3.13 The dimensions that used to measure HRQOL among the study sample 41 Table 3.14 Self-reported EQ-5D health states 42 Table 3.15 EQ-5D-5L index vs hemoglobin goal 44 ix List of Appendices No Contents Pages Appendix 1 2012 KDIGO Guideline 67 Table 1.1 2012 KDIGO recommendation for diagnosis of anemia 67 Table 1.2 2012 KDIGO recommendations for use of iron supplementation in patients with CKD 68 Table 1.3 2012 KDIGO recommendations for use of ESAs and other agents to treat anemia in CKD: ESA initiation 69 Table 1.4 2012 KDIGO recommendations for use of ESAs and other agents to treat anemia in CKD: ESA maintenance therapy 70 Table 1.5 2012 KDIGO recommendations for use of ESAs and other agents to treat anemia in CKD: ESA dosing, administration and frequency 70 Appendix2 Data Collection Form 71 Appendix 3 Institutional Review Board Approval Letter 77 Appendix 4 Ministry of Health Approval Letter 78 Appendix 5 An-Najah National University Hospital Approval Letter 79 x List of Symbols and Abbreviations CBC Complete Blood Count CKD Chronic Kidney Disease CrCL Creatinine Clearance DM Diabetes Mellitus EGFR Estimated Glomerular Filtration Rate ESA Erythropoietin Stimulating Agent ESRD End Stage Renal Disease EQ-5D-5L European Quality of Life- 5 Dimensions-5 levels Hb Hemoglobin HD Hemodialysis HRQOL Health Related Quality of Life KDIGO Kidney Disease: Improving Global Outcomes NKF-KDOQI National Kidney Foundation Kidney Disease/Dialysis Outcomes Quality Initiative PD Peritoneal Dialysis RBC Red Blood Cell TSAT Transferrin Saturation xi Evaluation of anemia management among hemodialysis patients in Palestine: associated factors and clinical outcomes By Nada Sadek Rajabi Supervisor Dr. Samah Al-Jabi Abstract Background: Anemia is a frequent complication in patients on maintaining hemodialysis (HD). Appropriate management involves the administration of iron supplementation and erythropoietin stimulating agents (ESA) therapy besides monitoring the response. Poor health related quality of life (HRQOL) is also a common impairment in HD patients results from the dialysis procedure it-self or its related comorbidity. This study aimed to evaluate anemia management in HD patients from Palestine, determine the associated demographic and clinical characteristics with it, describe patients HRQOL and its association with appropriate anemia treatment. Methods: The study was a cross sectional observational study; patients were included from three dialysis centers from West Bank - Palestine during the period of 24-June to 5-September 2018. The data filled by interviewing the enrolled patients and getting access to patient‘s health profiles. The data collection form consisted from two portions, the initial contains demographic and clinical information about the patients while the latest consists of the European Quality of Life 5- Dimensions scale (EQ- 5D-5L) that represents the descriptive system and the EQ visual analogue scale (EQ-VAS) which represents the health status of patient in their own judgment. xii Results: 226 patients included. Their mean age (± SD) was 57 ± 13.9 years. The mean hemoglobin (Hb) level (± SD) was 10.63 ± 1.71 g/dl, 1..3% of patients had Hb level 10-11.5 g/dl. Only 72.1% and 81.9% of patients recorded for serum ferritin and transferrin saturation (TSAT) respectively. 33.1% of patients had serum ferritin ≥ 500ng/ml and 50.3% had TSAT ≥ 30%. All patients who received iron supplementation received it by intravenous route and dose of 100mg of iron sucrose. Almost 86.7% of patients received Darbepoetin by intravenous route and weekly dose of 0.45 mcg/kg, 24% of them had Hb >11.5g/dl. On the other hand, 2.4% of patients had Hb < 10g/dl and did not received ESA therapy. Regarding EQ- 5D-5L 22.6%, 54.9%, 32.3%, 29.6% and 25.2% of patients had level of ―no problem‖ across the dimension of quality of life; mobility, self-care, usual activity, pain/ discomfort and anxiety respectively. Only 0.9% of patients had the highest degree of difficulty in the five dimensions. There was a significant association between Hb level, number of years the patients received HD and HRQOL. Conclusion: Our study found a significant association between Hb level and patients HRQOL, therefore the appropriate management of anemia in HD patients by adherence to NKF-KDOQI guideline recommendations provides an improvement in their quality of life in addition to obtain the optimal therapy. xiii Key word: Anemia, Hemodialysis, Hemoglobin, Iron status, Erythropoietin stimulating agent, Health related quality of life. 1 Chapter one Introduction 1.1 Background Hemodialysis (HD) is the backbone and life sustaining therapy for patients with ESRD who cannot undergo renal transplantation (Murtagh et al., 2007, Levey and Coresh, 2012, Chauhan and Mendonca, 2015). The overall stated number of patients with end stage renal disease (ESRD) undergoing HD in the West Bank of Palestine increased from 1014 in 2015 to 1119 patients in 2016, distributed in 12 units (Palestinian Ministry of Health, 2016, Palestinian Ministry of Health, 2017) Hemodialysis procedure can accomplish frequent complications related to ESRD (Himmelfarb, 2005). Anemia is a frequent complication among ESRD patients that affects almost all patients undergoing HD (Strippoli and Clinical Evaluation of the, 2010, Jiang et al., 2013). Anemia is one of the most common manifestations and visible characteristics of chronic kidney disease (CKD) contributing to mortality and morbidity (Al-Ali et al., 2015); adverse cardiovascular outcomes and poor health-related quality of life (HRQOL) (Strippoli and Clinical Evaluation of the, 2010). Managing anemia in patients received renal replacement therapy is contentious despite the availability of erythropoietin stimulating agents 2 (ESAs) which are considered as a standard therapy for anemia in CKD patients (Ornt et al., 2013, Al-Ali et al., 2015). On the other hand, HD can bring about significant impairment in HRQOL whether from the process of dialysis itself or its related comorbidity that affects patient`s social and psychological function (Zyoud et al., 2016). Furthermore, impaired HRQOL has been reported as a marker for poor outcomes in HD patients (Ibrahim and El Salamony, 2008, Mujais et al., 2009). In recent years, studies that intended to evaluate the treatment modalities and determined the mortality and morbidity in patients on HD; put greater interest in studying HRQOL among those patients (Lopes et al., 2002, Mapes et al., 2003). Deterioration of HRQOL increased over time, one of its anticipated factor was the changes in hemoglobin (Hb) level (Soni et al., 2010). Moreover, previous studies have suggested a correlation between HD, anemia and diminished HRQOL (Soni et al., 2010, Sadeghi et al., 2016). 1.1.1 Anemia in CKD Chronic kidney disease associated with serious complications that affects body homeostasis, one of the most common complications is anemia. Anemia of renal failure was first observed by Richard Bright (later Sir Robert Christison) in 1839; he noted that “by far the most remarkable character of the blood in the advanced stage of the Bright’s disease is a gradual and rapid reduction of its coloring” and “no other natural disease 3 came as close to hemorrhage for impoverishing the red particles of the blood.” Similarly, Richard Bright had noticed that patients with kidney disease had paleness of the skin: “after a time, the healthy color of the countenance fades‖ (Cameron, 1999) Anemia appears as early as stage 3 CKD (Alldredge et al., 2013); but relatively become more severe and frequent in more advanced stages of the disease (Fishbane and Spinowitz, 2018). Although, anemia is well identified as a complication of CKD, the association between the grade of renal insufficiency and the decline in hematocrit is not effectively defined. A study at Boston health clinics published in 2001 concluded that there is an apparent decrease in hematocrit level in patient with creatinine clearance (CrCL) ˂ 60 ml/min and men have larger decreased in hematocrit than women (Hsu et al., 2001). The Third National Health and Nutrition Examination Survey (NHANES III) (1988 to 1994); analyzed hemoglobin, iron profile and serum creatinine in order to asses iron status, quantify the relationship between hemoglobin level and the rate of reduction in kidney function and estimate the likelihood of anemia in adults patients (>18 years) with different stages of CKD (Hsu et al., 2002). The results showed that the reduction in hemoglobin level is contributed with even a mild decrease in kidney function. In addition, men have larger decreased in hemoglobin level than women at any given level of CrCL; the apparent decrease in hemoglobin 4 level begin when CrCL ≤ 70 ml/min in men and ≤ 50ml/min in women. For example, compared with subjects with CrCl > 80 ml/min, the decrease in hemoglobin for subjects with CrCl 20 to 30 ml/min was 1.0 g/dl in women and 1.4 g/dl in men. Results also demonstrate that 46% of women and 19% of men had transferrin saturation (TSAT) ˂ 20%; and 47% of women, 44% of men had serum transferrin ˂ 100ng/ml when CrCL between 20-30 ml/min (Hsu et al., 2002). On the other hand, the Kidney Early Evaluation Program (KEEP 2.0) from August 2000 to December 2001, measured serum creatinine in individuals with a high risk for developing kidney disease and patients with CKD and assessed the prevalence of anemia and diabetes at different stages of kidney function (El-Achkar et al., 2005). Results determined that 15.9%, 26.9% and 7.7% of the participants had diabetes, anemia and moderate decrease in kidney function (EGFR ˂ 60ml/min/1.73m 2 ) respectively. In addition, the study concluded that there is an independent correlation between anemia and diabetes in patients with different level of EGFR (EGFR ˂ 60ml/min/1.73m 2 ), and that the prevalence of anemia in men with diabetes is higher than that in women (El-Achkar et al., 2005). The main reason for anemia in patients with CKD is a reduced in red blood cell (RBC) production; as erythropoiesis depend on sufficient accessibility of both erythropoietin and iron (Thomas et al., 2008, Alldredge et al., 2013, Fishbane and Spinowitz, 2018). Erythropoietin: which is a glycoprotein produced by an approximately 90% from renal cortical interstitial, its 5 deficiency in CKD is the key limit for reduced RBC production in bone marrow. In addition, iron deficiency in patients with CKD occurred in more than fifty percent of non-dialysis patients and in greater percentage in patients receiving HD, with an estimated loss of more than 2000 mg of iron per a year through HD (Fishbane and Spinowitz, 2018). Other factors contributed to anemia in CKD in addition to diminished RBC production are shortened erythrocyte survival, blood loss, hemolysis, inflammation, infection, nutritional deficits, folate and vitamin B12 deficiency and underlying hematologic disease (Thomas et al., 2008, Alldredge et al., 2013, Fishbane and Spinowitz, 2018). 1.1.2 Symptoms and complication related to anemia in CKD Fatigue, shortness of breath, headache, reduced mental status and insomnia are nonspecific symptoms of anemia produced as a result of decrease oxygen supply to body tissues and organs (Thomas et al., 2008, Alldredge et al., 2013, Fishbane and Spinowitz, 2018). Cardiovascular complication is a consequence as anemia progresses in CKD patients, including angina, left ventricular hypertrophy (LVH) and heart failure (Thomas et al., 2008, Alldredge et al., 2013). LVH was detected in 30% of patients with stage 2 and 3 CKD and 74% at stage 5 CKD (Alldredge et al., 2013). 6 1.1.3 Diagnosis and evaluation of anemia in CKD The 2012 Kidney Disease: Improving Global Outcomes (KDIGO) guideline defines anemia in children > 15 years and adults with CKD as Hb ˂ 13.0 g/dl in males and ˂ 12.0 g/dl in females (Appendix 1,Table 1.1), (KDIGO Board Members, 2012). Hemoglobin testing should be performed periodically at all stages of CKD at different frequency manner based on the presence or absence of anemia, CKD stages, whether patient receiving ESA therapy or not and type of dialysis; HD or peritoneal dialysis (PD) (KDIGO Board Members, 2012). KDIGO recommended measuring Hb level in non-anemic CKD patients at least annually in stage 3, every 6 months in stage 4 and non-dialytic stage 5 and every 3 months in dialytic stage 5. In addition, for anemic patients not receiving ESA, Hb level is recommended to be monitored at least every 3 months from stage 3 to non-dialytic and PD stage 5 and monthly in HD patients (KDIGO Board Members, 2012). For initial evaluation of anemia, regardless the age and CKD stages, several blood tests are suggested to be performed including complete blood count (CBC), absolute reticulocyte count, iron indices, folate and vitamin B-12 serum level. Complete blood count results, involving red cell indices, platelet count, white blood cell count and differential, Hb concentration, indicated the severity of anemia. Absolute reticulocyte is simply provide an information 7 about the readiness of bone marrow to response to anemia and the effectiveness of erythropoietic proliferative activity (Fishbane and Spinowitz, 2018). On the other hand, macrocytic anemia resulted from folate or vitamin B-12 deficiencies, whereas microcytic anemia caused from iron deficiency. Assessment of iron status is crucial for initiation of iron replacement and before starting treatment with ESA, as the deficiency in iron is a precipitating factor that lead to ESA hypo responsiveness and therefor sub optimized anemia (Van Wyck et al., 1989). TSAT and serum ferritin are the most widely used tests for assessing iron status. Ferritin is an iron binding protein play an important role in iron hemostasis and intracellular iron storage while serum ferritin is indirectly reflects the total body iron stores (Wang et al., 2010), in addition TSAT which is calculated by divided the serum iron by total iron binding capacity demonstrate the percentage of transferrin protein that carry iron and assess the availability of circulating iron (Worwood and May, 2006). KDIGO recommended measurement TSAT and serum ferritin at least every 3 months during ESA administration and in more frequent pattern if ESA therapy initiation or increasing dose is required, monitoring response to iron repletion therapy and in any condition associated with iron depletion (Cattran et al., 2012), (KDIGO Board Members, 2012). 8 KDIGO 2012 recommended to achieve Hb level in adult 10-11.5 g/dl, serum ferritin ≥ 500ng/ml and TSAT ≥30% (KDIGO Board Members, 2012). 1.1.4 Treatment of anemia in CKD Several treatment approaches; blood transfusion, iron replacement and ESA therapy are clinically indicated for anemia management in CKD patients. Adequate iron availability is the most important components required for the effectiveness of ESA therapy and prevent worsening of anemia (Fishbane and Maesaka, 1997, Fishbane et al., 1996, Van, 1989). Administration of iron supplement is crucial in order to maintained its availability therefore treat its deficiency, prevent its declining with ESA therapy, increase Hb level in absence or presence of ESA and reduce the dose of ESA once indicated (KDIGO Board Members, 2012). According to KDIGO recommendation, iron therapy should be administered after assessing the benefits of its administration and the risk for potential adverse effect. Generally, either oral or intravenous rout of iron can be considered. The decision for initiation or continuing iron supplementation in patients receiving ESA required regular evaluation for TSAT and serum ferritin at least every 3 months (KDIGO Board Members, 2012). 9 In addition, the standard therapy for anemia in CKD is ESA, and its administration has a beneficial outcome in reducing blood transfusion which is associated with blood borne viral disease transmission and prolonged or even the failure the chance of kidney transplantation (KDIGO Board Members, 2012). Although ESA therapy is the mainstay treatment for anemia of CKD; its cost and poor response to ESA is considered as a challenge in the management of anemia. Several reasons influence the ESA hyporesponssivenes such as insufficient dialysis, blood loss, iron deficiency, hyperparathyrodism, inflammation, infection ,noncompliance and bone marrow disorder (Johnson et al., 2007, Zuo et al., 2016). The 2012 KDIGO recommendations for use of iron supplementation and ESA in patients with CKD are represented in Appendix 1, (Table1.2,1.3,1.4). 1.2 Statement of problem The most inclusive goal for the treatment of patients with ESRD is not only restricted on maintaining long survival rate, but also preserving patent‘s life at satisfactory level with improved quality of life (Seica et al., 2009). Good anemia control had a positive impact on HD patients including lower mortality and morbidity risk with a substantial improvement of HRQOL (Pisoni et al., 2004, Singh et al., 2006, Akel et al., 2017). 10 Anemia management in ESRD is a challenge for health care providers as well as for the patients themselves (Akel et al., 2017), whereas inappropriate management is associated with poor outcomes and HRQOL. Few studies have been done to evaluate the anemia management among patients on HD and its correlation with HRQOL, and fortunately, none of these studies were conducted in Palestine. This study may increase the knowledge about the disease and its management, aiding both the medical staff and the patients to improve their HRQOL. Moreover, this may help in decreasing therapeutic failure, the need for hospitalization and even death. 1.3 Research objectives 1.3.1 General objective The main objective of the current study was to evaluate anemia management among patient on maintenance HD. 1.3.2 Specific objectives: 1. To assess HRQOL of patients on HD including anemic patients. 2. To determine the demographic, clinical characteristics of the study patients that were associated with anemia in HD patient. 3. To assess the association between anemia and HRQOL, demographic characteristics and disease related factors in HD patients. 11 1.4 Significance of the study The previous studies aimed to define HRQOL association with HD (Zyoud et al., 2016), few studies have been established in order to study the management of anemia among patients on HD and it correlation to HRQOL (Soni et al., 2010, de Goeij et al., 2014). However, our study is the initial in Palestine focusing this issue. Therefore, this research gives a framework and information that evaluates anemia management, and data about anemia and its association with HRQOL, demographic and clinical characteristics of HD patients from Palestine. In addition, determination of HRQOL and other factors associated with low Hb level among HD patients and evaluation of the treatment strategy can help in improving the treatment approach of those patients. 1.5 Literature Review Anemia is a common feature of ESRD that is associated with poor outcomes including a reduction in HRQOL, increase the risk for hospitalization and death. In recent years, a greater interest has been introduced to study the appropriateness of anemia management strategies and to investigate the relationship between anemia and HRQOL (Pisoni et al., 2004). A study was performed in Saudi Arabia in 2008 aimed to review the management manner for anemia in HD patients and to check out its 12 appropriateness by comparing the noticed pattern to KDOQI guideline recommendation (Al-Ageel et al., 2012). This study was carried out over 7 months retrospectively and prospectively, the collected data included anemia status, iron administration, ESAs dosing besides patient‘s demographic and clinical characteristics. Study enrolled 87 patients on maintaining HD with a mean age 50 ± 14 years, and the majority of patients received HD for ≥ 2 years. In addition, diabetic nephropathy was the precipitating reason of ESRD and hypertension is the most common complication. The study found that 45% of patients had mean Hb level between 11.0 and 12.0 g/dl which is within the target range recommended by KDOQI, 30% between 10.0-11.0 g/dl, 10% lower than 10.0g/dl and 15% above 12.0g/dl. In addition, the mean dose of erythropoietin per week was 135 ± 99 IU/kg/week, the study proved that a smaller dose of erythropoietin used with higher Hb level. According to iron therapy and monitoring, only 81.6% of patients received iron replacement, 55.2% and 59.8% had recorded serum ferritin and TSAT value respectively. And 21.8% of patients were recorded for both ferritin and TSAT. The study also showed that females and patients with lower albumin level had a statistically significant lower Hb levels (Al-Ageel et al., 2012). The European Survey of Anemia Management 2003 (ESAM 2003) (Jacobs et al., 2005a), has been conducted in 11 European countries (Austria, Belgium, Finland, Germany, Greece, The Netherlands, Poland, Slovenia, 13 Sweden, Switzerland and the UK) and Israel. It aimed to judge the managing of anemia in ESRD after the development of The European Best Practice Guidelines (EBPG) for handling with anemia in patients with ESRD at 1998 and evaluate whether the management of anemia had enhanced after four years of its introduction. Collected data included patient‘s demographic characteristic, clinical characteristic including cause of renal failure, concomitant disease and type of dialysis, laboratory data and epoetin therapy. Results revealed that diabetic nephropathy is the most verified reason of renal failure, hypertension is the communal comorbidity and the majority of precipitants had received HD. In addition, 66.1% of participants had Hb level ≥ 11 g/dl, 36.7% ≥ 12 g/dl, however, 13.2% had Hb level below 10 g/d. The percentage of patients accomplished to target Hb level (≥ 11 g/dl) varied among countries with highest proportion in Switzerland, Sweden and Belgium, more than 75% of their patients reached the target. While lower proportion in Greece and Poland, less than 65% of patients achieved it, however Germany, Netherlands and the UK failed to reached the stated target hemoglobin in more than 65% of their patients. For patients who had treated with epoetin for more than 3 months, 65.7% of them had a target hemoglobin concentration. Moreover, iron status was available for 91% of surveyed patients. Overall 90.75% and 63.83% of precipitant had available serum ferritin and TSAT respectively. 89.7% had a serum ferritin ≥100 ng/ml and 31% had TSAT ˂ 20%. Only 48% of patients with epoetin therapy for more than 3 months had adequate iron status with serum ferritin ≥ 100 ng/ml and TSAT ≥20% as stated in EBPG. 14 Furthermore, in all countries the dose of epoetin was generally higher in patients not attained the goals of management compared with patients who achieved Hb level ≥ 11g/dl. In addition, the study concluded that there was an improvement in anemia management with EBPG, however many patients still have Hb level below the recommended. Thus, the study suggested that for better improvement there is a need for optimal iron supplementation and monitoring, adequate epoetin therapy and assessing the factors associated with its resistance (Jacobs et al., 2005b). Gulf Survey on Anemia Management (GSAM) (Alsuwaida et al., 2007) is a retrospective survey of adult patients with ESRD undergoing chronic dialysis, in six Arabian Gulf countries including Saudi Arabia, Kuwait, Bahrain, Oman, United Arab Emirates and Qatar. The survey was done to confirm the fulfillment of the clinicians in the Arabian Gulf countries in the management of anemia according to the practical international guidelines. In GSAM, diabetic nephropathy was the leading factors for ESRD, and hypertension was the most prevalence comorbidity followed by type 2 diabetes, ischemic heart disease and viral hepatitis. The mean Hb level was 11.5 ± 1.5g/dl; 28% had Hb levels ≥ 11.0 g/dL, 38% had a Hb levels ≥ 12.0 g/dL, and 16% had Hb levels <10.0 g/dL. In addition, from all countries only Bahrain achieved the target Hb level (≥11.0 g/dL) in more than 75% of patients, while in the other countries less than 65% achieved it. Moreover, according to iron status, serum ferritin level was available in 97% of patients; it was found that serum ferritin was ≥ 100 ng/ml in 90.5% of these patients. And 31% of patients with available TSAT level had 15 TAST below 20%. Only 63.8% of patients who had administered epoetin therapy for ≥ 3 months were having sufficient iron status with serum ferritin levels of ≥ 100 ng/ml and TSAT value of ≥ 20%. Moreover, the mean dose of epoetin varied among countries; higher doses were reported in Kuwait and Qatar; in contrast, lower doses were reported in Oman, while there was no significant difference in Hb level in these countries. A prospective, multicenter observational study that was conducted over 6 months between 2013 and 2014 in Lebanon at two dialysis centers in Beirut aimed to assess the adherence of anemia management to KDOQI guideline, evaluate the impact of iron status on Hb level and identify the relationship between Hb level and morbidity (Akel et al., 2017). The data enrolled from 189 HD patients, include patient‘s demographic and clinical information. The patients‘ mean age was 57.28 years, and 54.9% of patients were male, and the most common concomitant disease was hypertension. The study data demonstrated that the mean Hb level was 10.29 ± 1.44g/dl, 26% of patients had Hb level within the target range (11-11.9g/dl) as recommended by KDOQI. Furthermore, there was a significant difference between the recommended and prescribed dose of erythropoietin and iron replacement. In addition, erythropoietin weekly dose was 100 IU/Kg/week, which is approximately one third of the recommended starting dose by KDOQI (50-100 IU/kg three time weekly). Moreover, there is a significant difference with Hb level and different iron status (Akel et al., 2017). 16 A multicenter cross sectional and prospective study conducted in Iran (Nafar et al., 2017), investigated adult HD patients who received HD from January 2015 to December 2015. This study aimed to assess the status of anemia in HD patients, identify factor associated with erythropoietin responsiveness, assess the relationship between the dose of erythropoietin and response in Hb and identify the lowest dose of erythropoietin responsible for a gradual increase in Hb level toward target. The collected data included patient‘s demographic information, clinical characteristics; cause of ESRD, concomitant disease, years of dialysis, medication, type and dose of ESA and laboratory results. The results demonstrated that 62.3% of the enrolled patients were older than 55 years, 58.4% were men, 37% of patients were receiving dialysis for 12-36 months. The mean Hb level was 10.7 ± 1.4 g/dL, according to KDIGO guideline 54.5% the precipitant were within the target. In addition, 28.3% of recruited patients were anemic, 3% had Hb level ˂ 8g/dl and 17.2% had Hb level > 12g/dl. Furthermore, 95.5% of patients received ESA therapy, with a mean weekly dose 8180 ± 5001 IU/week (adjusted to body weight 128.5 ± 82 IU/kg/week). The total weekly dose of ESA was 4000-10000 IU in 52% of patients and a higher dose > 10000 IU in 33%. In this study the participants were categorized into 4 groups based on their Hb level; ˂ 8g/dl, 8-10 g/dl, 10-12 g/dl and > 12 g/dl, for assessing the association between ESA dose and Hb level. The highest dose of ESA was for patients with Hb ˂ 8g/dl and the lowest dose for patients with Hb > 12 g/dl. In addition, the effective dose of ESA for patients with Hb level 8-10 g/dl was 10000-12000 IU / 17 week. Moreover, 59.6 % of participants had adequate iron status, 31.8% had TSAT ˂ 20%, and 33.5% had serum ferritin ˂ 200 ng/ml. The results also conclude that, there was an association between lower Hb level and several factors include: younger patients, being female, patients received inadequate dialysis, malnutrition, low albumin level and elevated CRP value. Moreover, an observational retrospective cohort study conducted in Palestine over two months during 2014 at Hebron governmental hospital, aimed to determine the management strategies and its compliance to NKF- KDOQI and KDIGO guidelines for diabetes mellitus, hypertension, dyslipidemia, bone mineral disorder and anemia in HD patients. This study cited NKF-KDOQI 2006 and 2007 goals for anemia in HD with Hb 11-12 g/dl, serum ferritin >200 ng/ml and TSAT >20%, in addition KDIGO 2012 goals Hb 9 -11.5 g/dl, serum ferritin >500 ng/ml and TSAT > 30%. The total number of enrolled patients was 158, 60.1% were male, the mean age 49.6 ± 18 years. The highest proportion of patients was from village, had middle education level and were not working. 2 -18 medications with mean (±SD) 9.92 ± 2.94 were used by patients‘ sample, calcium carbonate was the most commonly prescribed followed by alfacalcidol then iron and folic acid. 69.9% of patients received iron supplementation and only 5.1% received ESA, the mean Hb level (± SD) was 8.84 ± 1.52 g/dl. Regarding to target; 8.9% and 43% achieved the Hb goals of NKF-KDOQI and KDIGO respectively. TSAT percentage were not available for all patients while serum ferritin level was obtained for 67.7%. 57.6% and 46.8% of 18 them had serum ferritin > 200 ng/ml and > 500 ng/ml as recommended by NKF-KDOQI and KDIGO respectively. Also, the study shows no significant association between control of anemia and patients sociodemographic and clinical factors (Al-Ramahi and Namourah, 2016). On the other hand, a cross sectional study carried out in Iran (Sadeghi et al., 2016) aimed to determine the relationship between anemia, HRQOL and some laboratory indices in HD patients. The collected data involved patient‘s demographic information, HRQOL questionnaire for patients on HD and laboratory results for sodium, potassium, calcium, phosphorus, creatinine, albumin, bilirubin and fasting blood sugar. According to patient‘s demographic characteristic, from 99 investigated patients 61.6% were male, the mean age was 5.98 ± 10.98 year and 63 patients were on dialysis for longer than 2 years. Results demonstrated a mean Hb level 10.36 ± 0.95 g/dL and hematocrit 32.60 ± 3.25%. The study also exhibited a positive significant correlation between Hb and hematocrit level with HRQOL. The results also showed a significant correlation between Hb and hematocrit level with albumin, bilirubin, potassium, calcium and phosphorous; while no significant correlation was found with glucose, creatinine and sodium. Furthermore, the use of erythropoietin resulted in an increased Hb level and subsequently an improvement in HRQOL. 19 Chapter Two Methodology 2.1 Study design and setting This study is a cross sectional observational study, achieved by using a convenience clustered sampling technique to address the research goals including the evaluation of anemia management in HD patients, assess HRQOL in these patients, to determine their demographic and clinical characteristics and assess the association between anemia and HRQOL, demographic characteristics and disease related factors in HD patients. The sample was recruited from three dialysis centers from West Bank - Palestine; An-Najah National University Hospital – Nablus, Ramallah's Sons Ward in Palestine Medical Complex – Ramallah and Al Hussein Government Hospital - Beit Jala. 2.2 Sample size The total number of patients who underwent dialysis at An-Najah National University Hospital, Ramallah's Sons Ward and Al Hussein Government Hospital by 2016 as reported in health annual report Palestine 2016 was 484 patients (Palestinian Ministry of Health, 2017). This number was used in calculating the sample size required for this study, using Roasoft sample size calculator (http://www.raosoft.com/samplesize.html), by means of response distribution 50% and 95% confidence interval margin of error 5%, the calculated minimum effective sample size was 216. http://www.raosoft.com/samplesize.html 20 An-Najah National University Hospital received 48.97% of this sample, Ramallah's Sons Ward received 32.44%, and Al Hussein Government Hospital received 18.59% of this population. Thus, the 216 patients were distributed as the following: 106 patients from An-Najah National University Hospital, 70 patients from Ramallah's Sons Ward and 40 patients from Al Hussein Government Hospital. Moreover, the estimated sample size was increased by 5% - 10% in order to maximize the reliability of the current study and decrease false results. Furthermore, a pilot study of 10 - 20 patients was done before beginning the actual study. 2.3 Data collection Data were collected from the three dialysis centers during the period from 24 June to 5 September 2018. The data were filled throughout the working time of each center by interviewing the enrolled patients for almost 10 min and then accessed their profiles. 2.3.1 Tools used in data collection A data collection form (Appendix 2) consists of two parts. The first part contains the patient‘s demographic and clinical information divided as the following: A. Socio-demographic characteristics including: age, gender, weight, height, level of education (illiterate, primary, secondary, university, postgraduate), family monthly income (low (less than 2000 NIS), moderate 21 ( 2000-5000 NIS), high (more than 5000 NIS)), marital status (married, single, divorced, widowed), locality (urban, rural, camp), employment status (unemployed, employed, previously employed before the failure onset), and family history of renal failure. B. Clinical information about disease history and co-morbidities which include: number of dialysis per week, years of suffering from renal failure, years of undergoing HD, the interval of dialysis session, smoking (current smoker, previous smoker, nonsmoker, years of smoking), exercise, using herbal remedies, and the presence of co-morbidities (such as hypertension, DM, ischemic heart diseases). C. Patient‘s current medications and last laboratory value. The second part consists of the European Quality of Life 5- Dimensions scale (EQ-5D). The Euro QOL Group developed the EQ-5 D instrument, which consists of the descriptive system and the EQ visual analogue scale (EQ-VAS). The descriptive system comprises five dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). In addition, EQ-VAS records the respondent‘s self-rated health on a 20 cm vertical visual analogue scale with endpoints labeled ‗the best health you can imagine‘ and ‗the worst health you can imagine‘. The EQ-VAS records how good or bad patient‘s health status is today by mark X on the scale and then write number on the box below. The Arabic version of EQ-5D was provided by using Euro QoL guidelines (Euroqol Group, 2013). 22 2.4 Inclusion and exclusion criteria 2.4.1 Inclusion criteria 1. ESRD patients on maintenance HD. 2. Patients aged 18 years and above. 3. Patients who agreed to participate. 2.4.2 Exclusion criteria: 1. Patients unable to understand the question, such as psychiatric patients. 2. Patients have cancer or are receiving chemotherapy. 2.5 Statistical analysis Through the Statistical Package for Social Sciences (SPSS; SPSS Inc., Chicago, IL, USA) program version 16 the overall data were entered and analyzed. The continuous variable was presented as mean and standard deviation, while categorical variable as frequency and percentage and variable that was not normally distributed was expressed as median (lower- upper quartile). The Kolmogorov-Smirnov test was used for testing the normality of variables. The Mann-Whitney U test (a nonparametric equivalent of the t test) / Kruskal–Wallis was performed as appropriate when the assumptions of equality of variance and normality (assumed for the t test) were not seen. Either the Chi-square or the Fisher exact test, as appropriate, was used to test significance between categorical variables. 23 The Spearman correlation coefficient was used for assessing correlation. The level of significance determined when p < 0.05. TSAT percentage that was not readily recorded was calculated for patients who had the available variables for its calculation; total serum iron, total iron binding capacity and serum transferrin. For analyzing the association between Hb and HRQOL, demographic characteristics and disease related factors; an average Hb level 11g/dl used as a cut of point for Hb goal. Additionally, the EQ-5D-5L Crosswalk Index Value Calculator, depending on values taken from the United Kingdom general population, was used for calculating the scores of EQ-5D. 2.6 Ethical Considerations Permission from the Institutional review Board (IRB), Palestinian Ministry of Health, and An-Najah National University Hospital (Appendices 2, 3, 4) were obtained before initiation the research. In addition, a verbal consent form was gained from patient individually and only patients who accepted to participate were included in the study. 24 Chapter Three Results 3.1 Demographic characteristics of the study sample A total number of 226 patients on HD included in this study. The data collected from three dialysis centers in West Bank, Palestine. The distribution of those patients was as follow: 108 (47.8%) patients were from An-Najah National University Hospital - Nablus, 74 (32.7%) were from Ramallah‘s Sons Ward in Palestine Medical Complex - Ramallah and 44 (19.5%) were from Al Hussein Government Hospital - Beit Jala. Table 3.1 shows the demographic characteristics of the patients. The mean age (± SD) of patients was 57 ± 13.9 years, ranging from 21 to 87 years. More than half of patients (n=121, 53.5%) were male. The largest portion (n=117, 51.8%) of patients were living in rural, followed by (n=86, 38.1%) urban areas. The marital status reported by patients was as the following: 78.8% were married and 21.2% were single/ divorced/ widowed. About the education level; the majority (n=86, 38.1%) of patients had secondary education, followed by (n=80, 35.4%) a primary education. A small proportion (n=13, 5.8%) of patients reported that they have current job, while 124 (54.9%) were previously employed. Furthermore, the mean weight (± SD) of patients was 75.65 ± 17.03 kg, ranging from 37 to 149 kg. The majority (n=136, 60.2%) of patients were non-smoker. Only 7.5% of patients did exercise. 25 On the other hand, out of 226 participants; 39 (17.3%) patients reported that they have family history of renal disease. Table 3.1 Demographic characteristics of the study sample Characteristic Total (n=226) Dialysis center, n (%) An-Najah National University Hospital – Nablus Al Hussein Ramallah‘s Sons Ward in Palestine Medical Complex – Ramallah Government Hospital - Beit Jala 108 (47.8) 74 (32.7) 44 (19.5) Gender, n (%) Male Female 121 (53.5) 105 (46.5) Age (years) Mean ± SD Range 57 ± 13.9 21-87 Age category (years) ˂ 30 30-60 > 60 13 (5.8) 111 (49.1) 102 (45.1) Locality, n (%) Rural Urban Camp 117 (51.8) 86 (38.1) 23 (10.2) Marital status, n (%) Married Single Divorced Widowed 178 (78.8) 27 (11.9) 2 (0.9) 19 (8.4) Level of education, n (%) Illiterate Primary Secondary University Postgraduate 19 (8.4) 80 (35.4) 86 (38.1) 38 (16.8) 3 (1.3) Employment status, n (%) Unemployed Employed Previously employed before renal failure 89 (39.4) 13 (5.8) 124 (54.9) Income of family, n (%) Low (less than 200 NIS) 6 (2.7) Weight (kg) Mean ± SD Range n=225 75.65 ± 17.03 37-149 Smoking, n (%) Current smoker Previous smoker Non-smoker 52 (23) 38 (16.8) 136 (60.2) Exercise, n (%) 26 Characteristic Total (n=226) No yes 209 (92.5) 17 (7.5) Family history, n (%) No Yes 187 (82.7) 39 (17.3) Abbreviations: NIS: new Israeli shekel, SD: standard deviation. 3.2 History of renal disease of the study sample As shown in Table 3.2, the median (interquartile range) of years that the patients had been suffering from renal failure and the years in which those patients undergoing HD was 4.0 (2.0 - 6.0) and 2.5 (1.0 - 5.0), respectively. In addition, the median number (interquartile range) of dialysis per week was 3.0 (3.0 - 3.0), with median of hours (interquartile range) of dialysis session was 3.5 (3.5 - 4). Table 3.2 History of renal disease of the study sample Variable Median (Interquartile range) Number of dialysis session per week 3 (3 - 3) Years of renal failure 4 (2 - 6) Years of dialysis 2.5 (1 - 5) Hours of dialysis 3.5 (3.5 - 4) 3.3 Herbal remedies used by the study sample The results show that 123 patients (54.4%) used herbal remedies; Arabic Gum (n=71,31%) was the most popular herbs used, followed by mixed herbs (n=42,18.6%) 27 Table 3.3 Herbal remedies used by the study sample Herbs Total (n = 226) n (%) Arabi gum 71 (31.4) Mixed herbs 42 (18.6) Parsley 18 (8) Anise 16 (7.1) Chamomile 11 (4.9) Honey 11 (4.9) Fenugreek 10 (4.4) Barely 10 (4.4) Rosemary 7 (3.1) Vervain 4 (1.8) Nigella 3 (1.3) Sage 3 (1.3) Frankincense 2 (0.9) Ginger 2 (0.9) Fennel 1 (0.4) Peppermint 1 (0.4) Tilia 1 (0.4) Thyme 1 (0.4) Radish 1 (0.4) Saffron 1 (0.4) Urtica 1 (0.4) Kefir 1 (0.4) Anabasis 1 (0.4) Teucrium 1 (0.4) 28 3.4 Comorbid diseases among the study sample The majority of patients suffered from hypertension (n=198, 87.6%), followed DM (n=127, 56.2%), (Table 3.4). Regarding to the presence of comorbid disease the median (interquartile range) of total number of comorbid diseases among patients was 4 (3-5.12). In addition, 0.4% of patients had no comorbid disease, 2.2% had only one comorbid disease, 11.5% had two comorbid diseases, 17.7% had three comorbid diseases and 68.1% had four and more comorbidities, (Table 3.5). Table 3.4 Comorbid diseases among the study sample Co-morbid disease Total (n = 226) n (%) Hypertensions 198 (87.6) Diabet1es Mellitus 127 (56.2) Ischemic heart disease 96 (42.5) Heart failure 61 (27) Hyperparathyroidism 48 (21.2) Dyslipidemia 40 (17.7) Gout 38 (16.8) Retinopathy 26 (11.5) Osteoarthritis 21 (9.3) Nephrotoxicity 20 (8.8) Urinary tract infection 19 (8.4) Urinary stones 15 (6.6) Hypothyroidism 12 (5.3) Polycystic kidney disease 10 (4.4) Atrophic kidney 9 (4) 29 Co-morbid disease Total (n = 226) n (%) Atrial fibrillation 7 (3.1) Benign Prostatic Hypertrophy (BPH) 6 (2.7) Asthma 5 (2.2) Gastroesophageal Reflux Disease (GERD) 4 (1.8) Osteoporosis 4 (1.8) Chronic Obstructive Pulmonary Disease (COPD) 3 (1.3) Hepatitis 3 (1.3) Glaucoma 3 (1.3) Familial Mediterranean Fever (FMF) 2 (0.9) Meniere‘s syndrome 2 (0.9) Systemic infection 1 (0.4) Rheumatoid arthritis 1 (0.4) Systemic Lupus Erythematosus (SLE) 1 (0.4) Glomerular Nephritis 1 (0.4) Crohn‘s disease 1 (0.4) Psoriasis 1 (0.4) Alport syndrome 1 (0.4) Hypoparathyroidism 1 (0.4) Table 3.5 Total diseases among the study sample Number of comorbid diseases Total (n = 226) n (%) No comorbid disease 1 (0.4) One comorbid disease 5 (2.2) Two comorbid diseases 26 (11.5) Three comorbid diseases 40 (17.7) Four and more comorbid diseases 154 (68.1) 30 3.5 Chronic medications used by the study sample Regarding medications used, the range number of medications used among patients was 0-14, with a mean (±SD) of 6.53 ± 2.37 and a median (interquartile range) of 6 (5-8). As shown in Table 3.6, according to patient's medications; Darbepoetin (n=196, 86.7%) Calcium carbonate (n=193,85.4%), Alfacalcidol (n=190,84.1%) and Iron III- hydroxide sucrose (n=128, 56.64%) were the most commonly used medications. Table 3.6 Chronic medications used by the study sample Medication Total (n = 226) n (%) Darbepoetin Dose (mcg): mean ± SD 30 mcg 60mcg 90mcg 196, (86.7) 42.1 ± 16.2 122 (62.2) 69 (35.2) 5 (2.6) Calcium carbonate 193 (85.4) Alfacalcidol 190 (84.1) Iron III- hydroxide sucrose (IV) Dose (mg) 128 (56.64) 100 Aspirin 102 (45.1) Amlodipine 80 (35.4) Ranitidine 75 (33.2) Insulin 66 (29.2) Atorvastatin 66 (29.2) Furosemide 64 (28.3) Sevelamer 55 (24.3) Paracetamol 42 (18.6) Bisoprolol 41 (18.1) 31 Medication Total (n = 226) n (%) Allopurinol 29 (12.8) Clopidogrel 26 (11.5) Isosorbide mononitrate 23 (10.2) Omega 3 18 (8) Enalapril 17 (7.5) Enoxaparin 16 (7.1) Carvedilol 13 (5.8) Doxazosin 12 (5.3) Atenolol 11 (4.9) L- Thyroxin 11 (4.9) Esomeprazole 9 (4) Folic acid 9 (4) Nifedipine 8 (3.5) Warfarin 8 (3.5) Loratadine 8 (3.5) Prednisolone 4 (1.8), Total (n= 225) Valsartan 4 (1.8) Hydralazine 4 (1.8) Omeprazole 4 (1.8) Colchicine 4 (1.8) Amlodipine / Valsartan 3 (1.3) Glimepiride 3 (1.3) Ipratropium Bromide 3 (1.3) Betahistine 3 (1.3) Cinacalcet 3 (1.3) Sodium valproate 3 (1.3) Phenytoin 3 (1.3) Labetalol 2 (0.9) Amiodarone 2 (0.9) L-Dopa 2 (0.9) 32 Medication Total (n = 226) n (%) Midodrine 2 (0.9) Vildagliptin 2 (0.9) Tamsulin 2 (0.9) Carbamazepine 1 (0.4), Total (n= 225) Lercanidipine 1 (0.4) Sacubitril / Valsartan 1 (0.4) Metolazone 1 (0.4) Metformin 1 (0.4) Saxagliptin 1 (0.4) Glibenclamide 1 (0.4) Pantoprazole 1 (0.4) Vitamin B-12 1 (0.4) Chlorpheniramine 1 (0.4) Montelukast 1 (0.4) Alfuzosin 1 (0.4) Bezafibrate 1 (0.4) Bisacodyl 1 (0.4) Gabapentin 1 (0.4) Pregabalin 1 (0.4) Clonazepam 1 (0.4) Abbreviation: IV: intravenous, SD: standard deviation 33 3.6 Hemoglobin level for the study sample As shown in Table 3.7, the mean Hb level (± SD) was 10.63 ± 1.71g/dl ranging from 6.10 to 17.31g/dl. According to anemia definition by KDIGO, 109 (90.1%) of male patients were anemic with Hb ˂ 13g/dl and 83 (79%) of female patients were anemic with Hb ˂ 12g/dl. With reference to KDIGO recommendation for Hb level, 84 (37.16%) patients had Hb value < 10g/dl, 134 (59.3%) patients had Hb value ˂ 11g/dl, 92 (40.7%) had Hb value > 11g/dl and 77 (34.1%) had Hb value 10-11.5g/dl which is within target level. Table 3.7 Hemoglobin level of the study sample Hb level (g/dl) Total (n=226)n (%) Mean ± SD Range 10.63 ± 1.71 6.10 – 17.31 Male Hb ˂ 13 Hb > 13 n= 121 109 (90.1) 12 (9.9) Female Hb ˂ 12 Hb > 12 n= 105 83 (79) 22 (21%) Hb ˂ 11 134 (59.3) Hb > 11 92 (40.7) Hb 10-11.5 77 (34.1) Hb < 10 84 (37.16) Abbreviation: Hb: Hemoglobin, SD: Standard deviation 34 3.7 Iron status monitored for the study sample As shown in table 3.6; out of 226 patients, 128 (56.6%) patients received iron replacement therapy via intravenous rout. All 128 patients used iron III -hydroxide sucrose with dose 100 mg. Information about iron status was available as the following; 163 (72.1%) patients had recorded serum ferritin and 185 (81.90%) had recorded TSAT (Table 3.8). The mean (±SD) TSAT of patients was 32.33 ± 17.16% ranging from 5.41 to 130, the mean (±SD) serum ferritin was 447.49 ± 464.45 ng/ml ranging from 4.63 to 2016. Relating to KDIGO goals, from 163 patients recorded for serum ferritin; 54 (33.1%) patients had serum ferritin ≥ 500 ng/ml. And from 185 patients recorded for TSAT 93 (50.3%) patients had TSAT ≥ 30%. Table 3.8 Iron status recorded for the study sample Lab test Total (n=226) Serum ferritin (ng/ml) n (%) Mean ± SD Range ˂ 500 ≥ 500 163 (72.1) 447.49 ± 464.45 4.63 – 2016 109 (66.9) 54 (33.1) TSAT (%) n (%) Mean ± SD Range ˂ 30 ≥ 30 185 (81.9) 32.33 ± 17.16 5.41 – 130 92 (49.7) 93 (50.3) Abbreviation: TSAT: Transferrin saturation, SD: Standard deviation 35 3.8 Erythropoietin stimulating agent used in the study sample The results show that 196 (86.7%) patients used Darbepoetin, the mean (± SD) administered dose was 42.1 ± 16.2 mcg. Among 196 patients; 122 (62.6%) patients received 30 mcg, 69 (35.2%) received 60 mcg and 5 (2,6%) received 90mcg (Table 3.6). Regarding to initiation of ESA; from the 30 patients (13.3%) who didn‘t receive ESA; 20% (n=6) had Hb level > 13g/dl as suggested by KDIGO not required to initiate of ESA. However, from 37.2% (n=84) of patients had Hb level < 10g/dl (Table 3.7), 2.4% (n=2) were not initiated with ESA therapy unless its recommendation according to KDIGO (Table 3.9). Regarding to maintaining use of Darbepoetin according to KDIGO, from the 196 patients who received it 24% (n=47) had Hb level > 11.5 g/dl which suggest not to maintain ESA use (Table 3.9). Table 3.9 Hemoglobin level and Darbepoetin administration in the study sample Hb level (g/dl) Total (n=226) Received Darbepoetin Hb > 11.5 Hb ≤ 11.5 196 (86.7) 47(24) 149 (76) Not received Darbepoetin Hb > 13 Hb <10 30 (13.3) 6 (20) 2 (2.4) Abbreviation: Hb:Hemoglobin 3.9 Some laboratory indices recorded for the study sample Table 3.10 shows a variety of laboratory results obtained for patients including c-reactive protein, albumin, total bilirubin, blood urea nitrogen, 36 fasting blood glucose, serum creatinine, phosphorous, calcium, potassium and sodium. Table 3.10 Some laboratory indices recorded for the study sample Lab test Total (n=226) C- reactive protein (mg/l) n (%) Mean ± SD Range 29 (12.8) 22.22 ± 50.49 0.49 – 272 Albumin (g/dl) n (%) Mean ± SD Range 182 (80.5) 3.82 ± 0.48 1 – 5.62 Total bilirubin (mg/dl) n (%) Mean ± SD Range 36 (15.9) 0.37 ± 0.15 0.2 – 0.8 Blood urea nitrogen (mg/dl) n (%) Mean ± SD Range 222 (98.2) 55.73 ± 54.85 4.30 – 728 Fasting blood glucose (mg/dl) n (%) Mean ± SD Range 109 (48.2) 140.69 ± 86.37 63 – 683 Serum creatinine (mg/dl) n (%) Mean ± SD Range 223 (98.7) 7.89 ± 3.08 0.92 – 21.3 Phosphorus level (mg/dl) n (%) Mean ± SD Range 225 (99.6) 10.71 ± 43.93 0.94 – 441 Calcium level (mg/dl) n (%) Mean ± SD Range 225 (99.6) 9.71 ± 8.12 6.14 – 95 Potassium level (mmol/l) n (%) Mean ± SD Range 224 (99.1) 4.71 ± 0.90 2.70 – 7.40 Sodium level (mEq/l) n (%) Mean ± SD Range 224 (99.1) 136.24 ± 13.07 3.92 – 154 Abbreviation: SD: Standard deviation 37 3.10 Socio-demographic characteristics of the study sample with differences in hemoglobin goal Table 3.11 show patient‘s demographic characteristics and its association with hemoglobin goal; there is no significant association between Hb goal and age category, gender, locality, level of education, marital status, employment status, being smoker, doing exercise and family history of renal disease with p-value > 0.05. Table 3.11 Demographic characteristics of patient sample vs hemoglobin goal n (%) Sociodemographic characteristics Total Hb ˂ 11g/dl Hb ≥ 11g/dl P-value Age category (years) < 30 30-60 >60 13 (5.8) 111 (49.1) 102 (45.1) 7 (5.2) 71 (53) 56 (41.8) 6 (6.5) 40 (43.5) 46 (50) 0.334 Gender Male Female 121 (53.5) 105 (46.5) 66 (49.3) 68 (50.7) 55 (59.8) 37 (40.2) 0.119 Locality Urban Rural Camp 86 (38.1) 117 (51.8) 23 (10.2) 53 (39.6) 65 (48.5) 16 (11.9) 33 (53.9) 52 (56.5) 7 (7.6) 0.391 Level of education Illiterate Primary Secondary University Postgraduate 19 (8.4) 80 (35.4) 86 (38.1) 38 (16.8) 3 (1.3) 12 (9) 47 (35.1) 52 (38.8) 23 (17.2) 0 (0) 7 (7.6) 33 (35.9) 34 (37) 15 (16.3) 3 (3.3) 0.334 Marital status Married Single Divorced Widowed 178 (78.8) 27 (11.9) 2 (0.9) 19 (8.4) 104 (77.6) 15 (11.2) 1 (0.7) 14 (10.4) 74 (80.4) 12 (13) 1 (1.1) 5 (5.4) 0.591 Employment status Unemployed Employed Previously employed before 89 (39.4) 13 (5.8) 124 (54.9) 55 (41) 9 (6.7) 70 (52.2) 34 (37) 4 (4.3) 54 (58.7) 0.555 38 n (%) Sociodemographic characteristics Total Hb ˂ 11g/dl Hb ≥ 11g/dl P-value renal failure Smoking Current smoker Previous smoker Non-smoker 52 (23) 38 (16.8) 135 (59.7) 33 (24.6) 18 (13.4) 83 (61.9) 19 (20.7) 20 (21.7) 52 (56.5) 0.227 Exercise No Yes 209 (92.5) 16 (7.1) 122 (91) 11 (8.2) 87 (94.6) 5 (5.4) 0.508 Family history No Yes 187 (82.7) 39 (17.3) 109 (81.3) 25 (18.7) 78 (84.8) 14 (15.2) 0.501 Abbreviation: IQR: Interquartile range, p-value: probability value, Hb: hemoglobin. 3.11 Disease related factors of the study sample with differences in hemoglobin goal As shown in table 3.12 there is no significant association between Hb target and number of dialysis per week, years of renal failure, total number of comorbid disease and chronic medications with p-value > 0.05. However, there is a significant association (p-value = 0.031) between hemoglobin target and number of years the patients undergo hemodialysis. 39 Table 3.12 Disease related factors associated vs hemoglobin goal n (%) Median (IQR) Disease related factors Total Hb ˂ 11g/dl Hb ≥ 11g/dl P-value Number of dialysis 1 2 3 4 1 (0.4) 24 (10.6) 199 (88.1) 2 (0.9) 0 (0) 15 (11.2) 117 (87.3) 2 (1.5) 1 (1.1) 9 (9.8) 82 (89.1) 0 (0) 0.399 Years of renal failure 4 (1.6525-6) 4 (2-6.75) 0.331 Years of dialysis 2 (1-5) 3 (1.3125-5) 0.031 Total disease cut off No comorbid disease One comorbid disease Two comorbid disease Three comorbid disease Four and more comorbid disease 1 (0.4) 5 (2.2) 26 (11.5) 40 (17.7) 154 (68.1) 0 (0) 1 (0.7) 13 (9.7) 25 (18.7) 95 (70.9) 1 (1.1) 4 (4.3) 13 (14.1) 15 (16.3) 59 (64.1) 0.190 Total number of medications No medication One medication 1 (0.4) 1 (0.4) 4 (1.8) 1 (0.7) 1 (0.7) 1 (0.7) 0 (0) 0 (0) 3 (3.3) 0.174 40 n (%) Median (IQR) Disease related factors Total Hb ˂ 11g/dl Hb ≥ 11g/dl P-value Two medications Three medications Four medications Five and more medications 14 (6.2) 29 (12.8) 177 (78.3) 5 (3.7) 20 (14.9) 106 (79.1) 9 (9.8) 9 (9.8) 71 (77.2) Abbreviation: IQR: Interquartile range, p-value: probability value, Hb: hemoglobin. 3.12 Health related quality of life of the study sample This study measured HRQOL among participants. Table 3.13 shows the dimensions that used to measure HRQOL that include: Mobility, Self-care, Usual activity, Pain/discomfort, and Anxiety. The majority of patients (n=66, 29.2%) had moderate problems in waking followed by 22.6% (n=51) with no problem in waking. The largest portion (n=124, 54.9%) had no problem regarding their self-care. According to patient‘s regular activity, 32.3% (n=73) and 23.9% (n=54) had no and slight problems doing their usual activities, respectively. Most of patients (n=74, 32.7%) experienced moderate pain or discomfort. About patients feeling of anxiety or depression; 27.4% (n=62), 26.5% (n=60) and 25.2% (n=57) were moderately, slightly and non-anxious or depressed respectively. 41 Table 3.13 The dimensions that used to measure HRQOL among the study sample Variable Total (n = 226) n (%) Mobility I have no problems in walking I have slight problems in walking I have moderate problems in walking I have severe problems in walking I am unable to walk 51 (22.6) 45 (19.9) 66 (29.2) 44 (19.5) 20 (8.8) Self-care I have no problems washing or dressing myself I have slight problems washing or dressing myself I have moderate problems washing or dressing myself I have severe problems washing or dressing myself I am unable to wash or dress myself 124 (54.9) 29 (12.8) 29 (12.8) 29 (12.8) 15 (6.6) Usual activity (e.g. work, study, housework, family or leisure activities) I have no problems doing my usual activities I have slight problems doing my usual activities I have moderate problems doing my usual activities I have severe problems doing my usual activities I am unable to do my usual activities 73 (32.3) 54 (23.9) 37 (16.4) 41 (18.1) 21 (9.3) Pain/Discomfort I have no pain or discomfort I have slight pain or discomfort I have moderate pain or discomfort I have severe pain or discomfort I have extreme pain or discomfort 67 (29.6) 41 (18.1) 74 (32.7) 25 (11.1) 19 (8.4) Anxiety/Depression I am not anxious or depressed I am slightly anxious or depressed I am moderately anxious or depressed I am severely anxious or depressed I am extremely anxious or depressed 57 (25.2) 60 (26.5) 62 (27.4) 33 (14.6) 14 (6.2) 42 3.13 Self-reported EQ-5D-5L health states and EQ-VAS Table 3.14 describes the reported health states of patients, 162 states were reported, 12 patients (5.3%) reported no difficulty in any of the five dimensions, while 2 patients (0.9%) reported the highest degree of difficulty in the five dimensions. The median (interquartile range) of EQ-5D-5L index was 0.69 (0.49-0.81) and for EQ-VAS score was 60 (50-75). Table 3.14 Self-reported EQ-5D-5L health states No. EQ- 5D Profile Total (n = 226) n (%) No. EQ- 5D Profile Total (n = 226) n (%) No. EQ-5D Profile Total (n = 226) n (%) 1 11111 12 (5.3) 55 24553 1 (0.4) 109 41111 1 (0.4) 2 11112 5 (2.2) 56 31111 1 (0.4) 110 41112 1 (0.4) 3 11113 1 (0.4) 57 31112 2 (0.9) 111 41133 1 (0.4) 4 11114 2 (0.9) 58 31113 1 (0.4) 112 41211 1 (0.4) 5 11121 2 (0.9) 59 31122 2 (0.9) 113 41214 1 (0.4) 6 11122 3 (1.3) 60 31123 1 (0.4) 114 41312 1 (0.4) 7 11123 2 (0.9) 61 31131 3 (1.3) 115 41343 1 (0.4) 8 11124 1 (0.4) 62 31133 1 (0.4) 116 41355 1 (0.4) 9 11131 3 (1.3) 63 31141 1 (0.4) 117 41434 2 (0.9) 10 11211 1 (0.4) 64 31143 1 (0.4) 118 41454 1 (0.4) 11 11213 1 (0.4) 65 31152 1 (0.4) 119 41512 1 (0.4) 12 11221 1 (0.4) 66 31211 1 (0.4) 120 42134 1 (0.4) 13 11222 2 (0.9) 67 31212 1 (0.4) 121 42242 1 (0.4) 14 11233 1 (0.4) 68 31222 1 (0.4) 122 42243 1 (0.4) 15 11234 1 (0.4) 69 31223 1 (0.4) 123 42311 1 (0.4) 16 11243 1 (0.4) 70 31231 1 (0.4) 124 42332 1 (0.4) 17 11311 1 (0.4) 71 31232 2 (0.9) 125 42423 1 (0.4) 18 11314 1 (0.4) 72 31233 2 (0.9) 126 42531 1 (0.4) 19 11322 2 (0.9) 73 31234 1 (0.4) 127 43232 1 (0.4) 20 11342 1 (0.4) 74 31244 1 (0.4) 128 43333 1 (0.4) 21 12222 2 (0.9) 75 31313 1 (0.4) 129 43343 1 (0.4) 22 12233 1 (0.4) 76 31325 1 (0.4) 130 43354 1 (0.4) 23 12332 1 (0.4) 77 31332 1 (0.4) 131 43431 1 (0.4) 24 13153 1 (0.4) 78 31334 1 (0.4) 132 43433 2 (0.9) 25 13333 1 (0.4) 79 31431 1 (0.4) 133 43521 1 (0.4) 26 15555 1 (0.4) 80 32211 1 (0.4) 134 43532 1 (0.4) 27 21111 4 (1.8) 81 32223 1 (0.4) 135 43544 1 (0.4) 28 21112 2 (0.9) 82 32232 1 (0.4) 136 44213 1 (0.4) 43 No. EQ- 5D Profile Total (n = 226) n (%) No. EQ- 5D Profile Total (n = 226) n (%) No. EQ-5D Profile Total (n = 226) n (%) 29 21113 1 (0.4) 83 32233 2 (0.9) 137 44231 1 (0.4) 30 21121 1 (0.4) 84 32322 2 (0.9) 138 44412 1 (0.4) 31 21122 5 (2.2) 85 32331 1 (0.4) 139 44413 2 (0.9) 32 21123 1 (0.4) 86 32334 1 (0.4) 140 44443 1 (0.4) 33 21124 1 (0.4) 87 32335 1 (0.4) 141 44444 4 (1.8) 34 21125 1 (0.4) 88 32353 1 (0.4) 142 44445 1 (0.4) 35 21131 1 (0.4) 89 32414 1 (0.4) 143 44554 1 (0.4) 36 21132 2 (0.9) 90 32433 1 (0.4) 144 45413 1 (0.4) 37 21133 1 (0.4) 91 33133 1 (0.4) 145 45525 1 (0.4) 38 21145 1 (0.4) 92 33231 1 (0.4) 146 45543 1 (0.4) 39 21211 5 (2.2) 93 33241 1 (0.4) 147 51135 1 (0.4) 40 21222 1 (0.4) 94 33311 1 (0.4) 148 51452 1 (0.4) 41 21224 1 (0.4) 95 33314 1 (0.4) 149 53313 1 (0.4) 42 21231 1 (0.4) 96 33323 1 (0.4) 150 53414 1 (0.4) 43 21232 2 (0.9) 97 33331 2 (0.9) 151 54412 1 (0.4) 44 21233 3 (1.3) 98 33333 2 (0.9) 152 54432 1 (0.4) 45 21331 1 (0.4) 99 33432 1 (0.4) 153 54433 2 (0.9) 46 21412 1 (0.4) 100 33432 1 (0.4) 154 54434 1 (0.4) 47 22213 1 (0.4) 101 33441 1 (0.4) 155 55452 1 (0.4) 48 22223 1 (0.4) 102 34412 1 (0.4) 156 55523 1 (0.4) 49 22232 1 (0.4) 103 34434 3 (1.3) 157 55533 2 (0.9) 50 22235 1 (0.4) 104 34443 1 (0.4) 158 55543 1 (0.4) 51 22312 1 (0.4) 105 34445 2 (0.9) 159 55552 1 (0.4) 52 23211 1 (0.4) 106 34452 1 (0.4) 160 55553 2 (0.9) 53 23211 1 (0.4) 107 34454 1 (0.4) 161 55554 1 (0.4) 54 24434 1 (0.4) 108 34533 1 (0.4) 162 55555 2 (0.9) 3.14 Correlation between EQ-5D-5L index and EQ-VAS There was a significant positive correlation (r = 0.444; P < 0.001) between the EQ-5D-5L index values and the reported EQ-VAS scores. 3.15 EQ-5D-5L index vs hemoglobin goal There is a significant association between quality of life and hemoglobin target with p-value 0.039, as shown in table 3.15. 44 Table 3.15 EQ-5D-5L index vs hemoglobin goal Median (IQR) Hb ˂ 11g/dl Hb ≥ 11g/dl P-value EQ-5D-5L index 0.646 (0.421-0.79) 0.7255 (0.50875-0.823) 0.039 Abbreviation: IQR: Interquartile range, p-value: probability value, Hb: hemoglobin. 45 Chapter Four Discussion Few studies have been established in order to study the management of anemia among patients on HD and its association with HRQOL (Soni et al., 2010, de Goeij et al., 2014). To the best of our knowledge, this study is the first in Palestine that aimed to provide a baseline data and information that aid to evaluate anemia management in HD patients and its association with HRQOL, patient‘s demographic and clinical characteristics. Most of socio-demographic findings of the current study were relatively closed to the results of an observational- retrospective cohort study that was conducted in ten hemodialysis units in the West bank, Palestine in 2015 that aimed to assess the prevalence of drug drug interactions in patients underwent HD (Al-Ramahi et al., 2016); the majority of interviewed patients were male, living in village and married, the average age ± SD was 50.67 ± 15.93 years in the previous study and 51.8% ± 13.9 years in the current study. In addition, 60.2% of patients in the current study were non- smoker whereas 78.9% of patients in the previous study were smoker (Al- Ramahi et al., 2016). In the current study, most patients had three dialysis sessions per week with a median length 3.5 hours of each session, similar findings were observed with a study conducted on HD patients in Palestine that aimed to define 46 factors affects quality of life in HD patients (Zyoud et al., 2016); 76.4% of patients received 3 session per week and the session lasts 3 hours in 74.2%. In the current study hypertension was the most co-comorbid disease in 87.6% of patients followed by DM (56.2%), and the maximum number of medications used by patients was 14, with a mean (± SD) 6.53 ± 2.37. Calcium carbonate was the most common medication used in 85.4% of patients followed by Alfacalclidol (84.1%). In addition the previous study by Al-Ramahi et al., (2016) had comparable findings; where hypertension was the most common co-morbidity (78.5%) followed by DM (42.5%). In addition, number of medications used by patients ranged from one to fifteen medications with a mean (± SD) 7.87 ± 2.44. And Calcium carbonate and Alfacalcidol were the most prescribed medications; 77.1% and 73.8% respectively. The finding of the current study differs from that of Saudi Arabia study in 2008 and Lebanon study in 2013. In Saudi Arabia, a study by Al-Ageel et al., (2012) enrolled from 87 patients from 2 HD centers over 7 months. In addition, in Lebanon Akel etal., (2017) the study conducted over 6 months between 2013 and 2014. The mean Hb level in our study (10.63 g/dl) was lower than that from Saudi Arabia (11.16 g/dl) and slightly higher than that from Lebanon study (10.29 g/dl). Both Saudi Arabia and Lebanon study measured compliance to KDOQI guideline which define target Hb 11-12 g/dl, however our study define target Hb level 10-11.5 g/dl based on KDIGO 2012 guideline. The percentage of patients with Hb lower than 47 11g/dl is higher in the current study (59.3%) compared to 45% in Saudi Arabia. Iron administration in HD patients is frequent, therefore the records for iron status is obligatory for the reason that iron deficiency is contributing to anemia, in addition to hypo responsiveness to ESA. In our study 56.6% of patients received iron therapy, all of them via intravenous route and a dose of 100mg Iron III- hydroxide sucrose. In addition, serum ferritin was recorded for 72.1% of patients, the mean (± SD) concentration for these patients was 447.49± 464.45 ng/ml and 33.1% of them had serum ferritin ≥ 500 ng/ml. Moreover, TSAT was recorded for 81.9% of patients with a mean 32.33 ± 17.16% and 50.3% of them had TSAT ≥ 30%. Whereas in the previous study in Saudi Arabia, 81.6% of patients received iron supplementation all via intravenous route (Al-Ageel et al., 2012). In addition, 55% of patients had serum ferritin concentration recorded with a mean (±SD) 693 ± 420.5ng/ml; and 91.7% of them had serum ferritin ≥ 200ng/ml. Furthermore, 59.8% of patients had TSAT recorded with a mean (±SD) 38± 19.7% and 88.5% of them had TSAT ≥ 20%. ESA is regularly initiated when Hb level between 9-10 g/dl as recommended by KDIGO, and it suggested not to maintain Hb >11.5g/dl, since increasing Hb >11.5-13g/dl in HD patients may associated with increased impairment such as an increased risk for thrombosis of the vascular access, stroke and hypertension (Cattran et al., 2012, Cases et al., 2018). In this study 37.16% of patients had Hb level < 10g/dl, 2.4% of 48 them were not initiated the ESA as recommended by KDIGO. Moreover, 24% from 86.7% of patients who received ESA had Hb level > 11.5g/dl, and KDIGO recommended not to maintain the ESA in those patients. On the other hand, in the current study, the mean (±SD) administered dose of Darbepoetin alpha was 42.1 ± 16.2 mcg. 62.6%, 35.2% and 2.6% of patients who received Darbepoetin were administered 30mcg, 60mcg and 90mcg respectively, once weekly by intravenous route. In the current study, 76% of patients who received ESA had Hb level ≤ 11.5g/dl, and those require maintaining ESA and should be assessed for ESA hypo responsiveness. Several reasons influence with hypo responssivenes such as iron deficiency, blood loss, noncompliance, infection, inflammation, hyperparathyroidism, inadequate dialysis and bone marrow disorder (Johnson et al., 2007). Our study shows no significant association between Hb level and any of demographic characteristics documented from patients. The previous study from Saudi Arabia revealed comparable results that there was no significant association between age and Hb level; however, females have statistically significant lower Hb level (Al-Ageel et al., 2012). Also a study conducted in Iran, aimed to assess the adherence to KDOQI guideline and evaluate the relationship between Hb and morbidity (Nafar et al., 2017), showed that younger age was associated with hemoglobin levels lower than 10 g/ dL. On the other hand, a study enrolled 169 patients during 12 months at a single center at Turkey; aimed to determine the factors 49 affecting Hb variability with inflammatory and nutritional conditions and its associations with all-cause mortality among hemodialysis patients found that the variability in Hb is positively correlated with age (Bal et al., 2018). On the other hand, the current study demonstrated no significant association between Hb level and number of dialysis session the patients received per week, years of suffering from renal failure, total number of comorbid disease and chronic medications. However, there is a significant association between number of years the patients undergo hemodialysis and hemoglobin target; as patients on chronic hemodialysis become more susceptible to bleeding during dialysis procedure as well as regular blood testing, anticoagulant administration and through intestinal hemorrhage moreover reduced dietary intake duo to diet restriction or loss of appetite all are associated with iron deficiency, consequent anemia and resistance to ESA (Motonishi et al., 2018), (Diebold and Kistler, 2019). However, Al- Ageel et al., (Al-Ageel et al., 2012) revealed no significant association between years of dialysis and Hb level. By comparing our study with the observational retrospective cohort study that conducted at Hebron governmental hospital during 2014 aimed to evaluate the compliance to treatment guidelines and goals of therapy for diabetes, hypertension, dyslipidemia, bone mineral disorder and anemia, in the mentioned study NKF-KDOQI and KDIGO guidelines were used, the mean Hb level was 8.84 ± 1.52 g/dl, the NKF-KDOQI Hb goals achieved only in 8.9% of patients and regarding to KDIGO goals as stated in their 50 study 43% of patients had Hb level between 9-11.5g/dl and not exceeded 13g/dl. None of patients had available TSAT and 32.3% had no recorded serum ferritin level. 57.6% and 46.8% had serum ferritin > 200 ng/ml and > 500 ng/ml as recommended by NKF-KDOQI and KDIGO respectively. Iron supplementation used by 69.9% of patients and only 5.1% used ESA as it was not available during the study period due to financial problem at MOH (Al-Ramahi and Namourah, 2016). However, our study showed unlike results by mean Hb level 10.63 ± 1.71 g/dl, Hb goals (10-11.5 g/dl) achieved by 34.1% of patients, moreover 72.1% and 819% of patients had available serum ferritin and TSAT respectively, 33.1% and 50.3% achieved goals of serum ferritin (≥ 500 ng/ml) and TSAT (≥ 30%) respectively. 56.6% of patients received iron replacement and 86.7% received ESA, the reasons for fluctuation between both studies may related to that the previous study conducted over a period by which MOH weren‘t able to provide ESA therapy as well as performed at one dialysis center (Al- Ramahi and Namourah, 2016). In the current study the median (interquartile range) of EQ-5D-5L index and EQ-VAS score were 0.69 (0.49-0.81) and 60 (50-75) respectively. While finding of EQ-5D-5L index and EQ-VAS score from a study conducted in Palestine were 0.41 (0.06-0.77) and 50 (50-70) (Zyoud et al., 2016). This difference might be due to the differences in the centers included in both studies. On the other hand, Zyoud et al., (2016) and the current study showed positive correlation between EQ-5D-5L index values and the reported EQ-VAS scores. 51 Regarding the dimensions of quality of life in this study, 5.3% of patients reported no difficulty in any of the five dimensions; however, 0.9% reported the highest degree of difficulty in the five dimensions. Moreover, the percentage of patients had no problem across the dimension of quality of life mobility, self-care, usual activity, pain/discomfort, and anxiety was as following: 22.6%, 54.9%, 32.3%,29.6% and 25.2% respectively. On the other hand, in the earlier study, Zyoud et al., (2016) found that 6.4% of patients reported no difficulty in any of the five dimensions but 3.4% reported very sever difficulty in the five dimensions. And the percentage of patients had no problem across the dimension of quality of life mobility, self-care, usual activity, pain/discomfort, and anxiety was as following: 27.3%, 54.7%, 37.5%,25.5% and 35.2% respectively (Zyoud et al., 2016). This study found a significant association between quality of life and hemoglobin target. Similar finding with a study carried out in Iran, aimed to determine the relationship between anemia, HRQOL and some laboratory indices (Sadeghi et al., 2016), showed a significant correlation between Hb and HRQOL. Moreover, a cross sectional study investigated at seven centers in Canada and United states during 2003-2006; aimed to study the relationship between the severity of anemia and quality of life in CKD patients (stage 3-5) by kidney disease quality of life questionnaire (Finkelstein et al., 2009). The study revealed that patients with an increased level of Hb from 11-13 g/dl had a significant improvement in their quality of life. In contrast a cross sectional study conducted in 2007 in Western China investigated HRQOL among hemodialysis patients via EQ-5D-3L, 52 by which each of 5 dimension has 3 level of no problem, some problem or extreme problem, showed no significant association between EQ-5D score and hemoglobin level (Yuan et al., 2019). 53 Chapter Five Conclusion 5.1 Strengths and limitations To the extent of our knowledge, this research is the first in Palestine regarding studying the management of anemia in HD patients and determination of its association with patient‘s HRQOL, demographic and clinical characteristics. Furthermore, the data were conducted by face-to- face interview and patients medical record provided comprehensive dependable data. However, our study had few limitations; First, it‘s a cross sectional study with short follow up period making the reason and outcome not well established and the resulted associations difficult to be interpreted. Second, the sample size was selected by a convenience sampling technique which may disturb the finding generalizability. Third, as the mainstream data conducted via face-to-face interview, bias could be announced. Although, face-to-face interview provide accurate screening, offer the capture of verbal and non-verbal question that show the level of discomfort with question and capture the behavior and emotions. Lastly some clinical variables such as; parathyroid hormone level, the presence of infection inflammation and blood factors that may be responsible of altering in Hb level and ESA hyporesponsiveness were not determined in our study. 54 5.2 Conclusion Our study finds that more than half of patents had Hb level below the target recommended by KDIGO therefore required routinely monitoring of Hb level for early evaluation of anemia. Approximately half of patients received iron replacement supplementation moreover most of them received ESA therapy while only 72.1% and 81.9% of patients had recorded serum ferritin and TSAT respectively, high percentage of patients had Hb level below target unless they received ESA in addition 2.4% of patients had Hb below 10g/dl and did not received ESA, consequently for cost effectiveness and optimal management we need precise defining the underlying causes, choosing the most desirable therapy and regular follow up for assessing the variables associated with inadequate response; recording iron status and Hb level. Furthermore, our study finds a significant association between Hb level and patients HRQOL, in conclusion, appropriate management of anemia in HD patients by adherence to KDIGO guideline recommendations provides an improvement in their quality of life likewise obtains the optimal therapy. 5.3 Recommendation - Based on thesis conclusion we recommended routinely assessment of anemia by regular measuring of Hb level among patients on maintaining HD, in addition regular recorded iron status for anemic patients. 55 - Nephrologist and clinical pharmacist have to select the most effective and suitable treatment approaches and assess patient‘s response and express factors related to inadequate response. - To better understanding the implications of these results, future study could address in Palestine in order to define clinical factors that alter Hb level and responsible for inadequate response. 56 References  AKEL, M., SHAMAS, K., SAKR, F., DABBOUS, M., SAFWAN, J., CHERFAN, M. & ISKANDARANI, M. 2017. 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N., MEZYED, D. O., KHDEIR, R. L., SAWAFTA, M. N., AYASEH, N. A., TABEEB, G. H., SWEILEH, W. M., AWANG, R. & AL-JABI, S. W. 2016. Factors affecting quality of life in patients on haemodialysis: a cross-sectional study from Palestine. BMC nephrology, 17, 44. 67 Appendices Appendix 1 2012 KDIGO Guideline Table 1.1: 2012 KDIGO recommendation for diagnosis of anemia (KDIGO Board Members, 2012) 1.2.1: Diagnose anemia in adults and children >15 years with CKD when the Hb concentration is ˂13.0 g/dl (˂130 g/l) in males and ˂12.0 g/dl (˂120 g/l) in females. (Not Graded) 1.2.2: Diagnose anemia in children with CKD if Hb concentration is ˂11.0 g/dl (˂110 g/l) in children 0.5–5 years, ˂11.5 g/dl (115 g/l) in children 5–12 years, and ˂12.0 g/dl (120 g/l) in children 12–15 years. (Not Graded) 68 Table 1.2: 2012 KDIGO recommendations for use of iron supplementation in patients with CKD. (KDIGO Board Members, 2012) 2.1.1: When prescribing iron therapy, balance the potential benefits of avoiding or minimizing blood transfusions, ESA therapy, and anemia related symptoms against the risks of harm in individual patients (e.g., anaphylactoid and other acute reactions, unknown long-term risks). (Not Graded) 2.1.2: For adult CKD patients with anemia not on iron or ESA therapy we suggest a trial of IV iron (or in CKD ND patients alternatively a 1–3 month trial of oral iron therapy) if (2C):  an increase in Hb concentration without starting ESA treatment is desired* and  TSAT is ≤30% and ferritin is ≤500 ng/ml (≤500 mg/l) 2.1.3: For adult CKD patients on ESA therapy who are not receiving iron supplementatio