Anemia in patients with chronic kidney disease

TRISAKTI UNIVERSITY FACULTY OF MEDICINE

M.Agung Santara 03009139 Jakarta 2012

PREFACE

First of all, I would like to gratitude for the presence of Allah SWT, the top of His grace, so the writer can complete the preparation of a paper titled Anemia in patients with chronic kidney disease. This paper is written as a part of my duty for completing the task of English 3. In this paper, i intend to explain about anemia in chronic kidney disease since this kind of disease is one of the most common problem in this world In writing this paper the author feel there are still many mistake both in technical writing and matter, in view of the capabilities of the author. Therefore, criticism and suggestions from all parties is the author of hope for the sake of improving the manufacture of this paper. In writing this paper the authors expressed his gratitude to the countless parties who assist in completing this study, particularly to the dr. Maskito A. Soerjoasmoro, MD, MS, PhD, as the supervisor, as well as all the parties can not mention individually, who have provided assistance in writing this paper. Finally, the author hopes may Allah reward in kind to those who have provided assistance, and can make all the help it as worship. I hope that this paper can provide adequate information for the readers. Finally, I apologize if there are some mistakes in this paper, and I am looking forward any suggestions and criticisms to improve in the future.

Jakarta, 12 June 2012

Abstract

Background : Chronic kidney disease is a worldwide public health problem. Patients with chronic kidney disease stages 1-3 are generally asymptomatic,. Its manifestations typically appear in stages 4-5. Early diagnosis and treatment of the underlying cause is decisive in patients with chronic kidney disease. Anemia is an almost constant complication of chronic renal failure that significantly contributes to the symptoms and complications of the disease. The anemia of chronic renal disease is caused by failure of renal excretory and endocrine function. Objective: We should view the management of anemia in these patients as part of the overall management of the many clinically relevant manifestations of chronic kidney disease. Conclusion: Erythropoiesis-stimulating agents are safe and should be used for treating anemia. It may prevent some of target organ damage of chronic kidney disease.

Keyword: anemia, chronic kidney disease, anemia in patient with chronic kidney disease

CONTENTS Title....... 1 Preface........................................................................................................................................2 Abstract......................................................................................................................................3 Chapter 1. Introduction 1 1.1 Background....... 6 1.2 Problem......... 7 1.3 Limitation of Problem........... 7 1.4 Purpose ......8 1.5 Method of Writing .........8 1.6 Frame of Writing ......... .8

Chapter 2 2.1 chronic kidney disease 2.1.1. Definiton....................................................9 2.1.2. Etiology..............9 2.2 Anemia 2.2.1 2.2.2 2.2.3 2.2.4 2.2.5 2.2.6 2.2.7 Definition.................................11 Etiology and Pathogenesis ..... 11 Blood loss.........................................................................11 Vitamin deficiences..........11 Uremic milleau........ 11 Epo deficiency..................................................................................................12 Iron deficiency..................................................................................................13 4

2.2.8

Inflamation.......................................................................................................14

Chapter 3. Discussion ..........15 Chapter 4. Conclusion ..,,....21 References ...........................22

CHAPTER 1. INTRODUCTION

1.1 Background

Chronic kidney disease (CKD) is a worldwide public health problem. It is recognized as a common condition that is associated with an increased risk of chronic renal failure (CRF). In the United States, there is a rising incidence and prevalence of kidney failure. Data from the United States Renal Data System (USRDS) indicated that the prevalence of chronic renal failure increased 104% between the years 1990-2001.(1) The onset of anemia in CKD is gradual and patients may not realize they have a problem. They may attribute fatigue and weakness to stress or not getting enough sleep. Patients who are anemic have less energy and enthusiasm. They do not want to finish projects because they are tired, weak and cannot concentrate. If the anemia is severe, dizziness may be present.(2) If left untreated, the anemia of CKD is associated with several abnormalities. These include deterioration in cardiac function, decreased cognition and mental acuity, fatigue, and other signs and symptoms. There are also associations with an increased risk of morbidity and mortality, principally due to cardiac disease and stroke.(3) By understanding the mechanism of chronic kidney failure that makes anemia and it is correlation, we could anticipate the patient from anemia symptoms. It is important to prevent the patient from the worsening outcome of anemia

1.2 Problem The reason why it is important to present anemia in chronic kidney disease because it has been a worldwide problem. People who is suffering from chronic kidney disease is usually asymptomatic especially in earlier stages. they may not realize it. anemia is the symptomps in people who is suffering from chronic kidney disease.

1.3 Limitation of Problem My paper is limited in terms of determinants and the pathophysiological mechanisms that may explain the association between anemia and chronic kidney disease. Many factors and mechanisms which can make anemia and chronic kidney disease. In this case, differences in the pathophysiological point of view that will be raised and discussed by the author. anemia is usually associated with chronic kidney disease, anemia is an almost constant complication of chronic renal failure that significantly contribute to the symptoms and complications of the disease. Anemia of chronic kidney disease caused by kidney failure excretory and endocrine functions. We must look at the management of anemia in these patients as part of the overall management of many relevant clinical manifestations of chronic kidney disease. erythropoiesis-stimulating agent is safe and should be used to treat anemia. This may make some target organ damage from chronic kidney disease and all concerned will be discussed in this paper.

1.4 Purpose The purpose of this paper is to find out more detail and discuss the determine factors of both diseases in a variety of viewpoints. Anemia is an almost constant complication of chronic renal failure that significantly contributes to the symptoms and complications of the disease. The purpose of this paper is also to studies the symptoms indicated anemia and chronic kidney disease

1.5 Method of Writing The method used by me as a writer is a review of the literature. Authors seek references from the articles and medical journals, which are related to this topic. Author of the reference tools of the internet and some books. in the context of the source, the author found the source of which was published less than ten years. Tools the author of several medical sites and some sites that have links with the science of this topic. Then, the author Mades review of references. In the end, the authors make conclusions from the opinions of exgftfperts who conduct research on anemia and chronic kidney disease.

1.6 Frame of Writing This paper contents five chapters. Chapter 1 is about Introduction. Its include background, problems, limitation of problems, purpose, methode of writing and frame of writing. In chapter 2, writer will talk about chronic kidney diseases and anemia which is include definiton,etiology and the others. In addition, the authors will also explain about how to work up anemia in patients with chronic kidney disease. The discussion that explains the correlation between anemia and chronic kidney disease and about the concept of

hematopoiesis will be explained in chapter 3. The conclusion will be discussed in chapter 4. 8

CHAPTER 2. LITERRATURE REVIEW

2.1 chronic kidney disease 2.1.1 Definition CKD is defined by the National Kidney Foundation as either kidney damage or a glomerular filtration rate (GFR) less than 60 mL/min/1.73 m2 for three months or more. Kidney damage is defined by pathological abnormalities or markers of kidney damage, including abnormalities in the composition of the blood or urine or abnormalities in imaging tests. Table 1. Stages of Chronic Kidney Disease Stage Description Slight kidney damage with normal or increased filtration Mild decrease in kidney function Moderate decrease in kidney function Severe decrease in kidney function Kidney failure GFR* mL/min/1.73m2 More than 90 60-89 30-59 15-29 Less than 15 (or dialysis)

1 2 3 4 5

*GFR is glomerular filtration rate, a measure of the kidney's function

2.1.2 Etiology There are numerous causes of CKD, ranging from inflammations such as glomerulonephritis to congenital abnormalities such as certain polycystic kidney diseases. However, the most common causes of CKD are diabetes and hypertension.

Diabetes may affect the kidneys in two ways. One is by damaging the blood vessels inside the kidneys; the other is through nerve damage. If the blood vessels in the kidney are damaged, they cannot properly filter all the waste products out of the blood appropriately. If diabetes damages the nerves of the bladder this may lead to increased pressure in the bladder due to incomplete emptying. The increased pressure in the bladder can back up and result in injury to the kidneys.

Hypertension is unique in that it can cause CKD or be the result of it. Hypertension can cause damage to the arteries resulting in insufficient blood flow to the kidneys, leading to CKD. One function of the kidney is to produce hormones to help regulate blood pressure. When CKD is present, hypertension may result due to a disruption to this process.(4)

In stage 1 and stage 2 chronic kidney disease, GFR alone does not clinch the diagnosis. Other markers of kidney damage, including abnormalities in the composition of blood or urine or abnormalities on imaging studies, should also be present in establishing a diagnosis of stage 1 and stage 2 chronic kidney disease. The K/DOQI definition and classification of chronic kidney disease allow better communication among physicians and facilitate intervention at the different stages. Patients with chronic kidney disease stages 1-3 are generally asymptomatic; clinically manifestations typically appear in stages 4-5. Early diagnosis and treatment of the underlying cause and/or institution of secondary preventive measures is imperative in patients with chronic kidney disease. These may delay, or possibly halt, progression. The medical care of patients with chronic kidney disease should focus on the following:

Delaying or halting the progression of chronic k idney disease Treating the pathologic manifestations of chronic kidney disease Timely planning for long-term renal replacement therapy(5)

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2.2 Anemia 2.2.1 Definition Anemia is a medical condition in which the red blood cell count or hemoglobin is less than normal. The normal level of hemoglobin is generally different in males and females. For men, anemia is typically defined as hemoglobin level of less than 13.5 gram/100 ml and in women as hemoglobin of less than 12.0 gram/100 ml. These definitions may vary slightly depending on the source and the laboratory reference used.

2.2.2 Etiology and pathogenesis Factors likely contributing to anemia in chronic kidney disease include blood loss, shortened red cell life span, vitamin deficiencies, the uremic milieu, erythropoietin (EPO) deficiency, iron deficiency, and inflammation. Unfortunately, we know little about the relative contributions of the different factors and conditions in the early stages of chronic kidney disease.(6) 2.2.3 Blood loss Patients with chronic kidney disease are at risk of blood loss due to platelet dysfunction. The main cause of blood loss is dialysis, especially hemodialysis, and the loss results in absolute iron deficiency. Hemodialysis patients may lose 3 to 5 g of iron per year. Normally, we lose 1 to 2 mg per day (FIGURE 1), so the iron loss in dialysis patients is 10 to 20 times higher. Therefore, iron supplementation is a mainstay of anemia management.(6) 2.2.4 Vitamin deficiencies It is difficult to determine whether vitamin deficiencies play a significant role in causing anemia in chronic kidney disease. Most patients with chronic kidney disease take a multivitamin daily, although there is no strong evidence that this is beneficial. Therefore, even the prevalence of vitamin deficiencies in chronic kidney disease has been hard to establish.(6)

2.2.5Uremic milieu The uremic milieu is a term that is overused in attempts to explain the multiple organ dysfunction of chronic kidney disease. In studies in vitro, the term has been invoked 11

when cultured cells were exposed to serum from patients with chronic kidney disease, with results that mimicked some of the clinical observations. For example, uremic serum has been shown to inhibit primary bone marrow cultures of early erythroid cell lines. However, the lack of specificity in these stud-ies has been criticized because this serum also affects other cell lines. In studies in vivo, the concept of a uremic milieu may explain why the level and prevalence of anemia correlate with the severity of the kidney disease. A GFR lower than 60 mL/minute/1.73 m2 has been associated with a higher prevalence of anemia, which reached 75% in some studies. In addition, in a study in patients who had been receiving hemodialysis, the hematocrit rose when the intensity of dialysis was increased, implying that reducing uremia restores or improves bone marrow function. However, this study could not distinguish the independent effects of the increased dialysis dose and the effect of changing to a more permeable dialysis membrane during the study.(7)

2.2.6 EPO deficiency EPO deficiency is considered the most important cause of anemia in chronic kidney disease. Researchers postulate that the specialized peritubular cells that produce EPO are partially or completely depleted or injured as renal disease progresses, so that EPO production is inappropriately low relative to the degree of anemia. Thus, measuring EPO levels in this population is of no use and should not be ordered: in fact, it can even be misleading if the value is normal when it ought to be high. However, the reason for this inappropriately low EPO production is not well understood. EPO is produced when its gene is transcribed, in a process that depends on the bind-ing of a molecule called hypoxiainducible factor 1 alpha to the hypoxia responsive element on the erythropoietin gene. Production of this factor increases in states of relative oxygen deficiency. Therefore, the balance between oxygen supply and consumption determines the production of hypoxia inducible factor 1 alpha and, in turn, production of EPO. Donnelly proposed that the relative EPO deficiency in chronic kidney disease could be a functional response to a decreased glomerular filtration rate.(8) The theory is that the EPO producing kidney cells themselves may not be hypoxic: if the glomerular filtration rate is low, there is less sodium reabsorption and sodium reabsorption is the main determinant of oxygen consumption in the kidney. In this situation there may be a local relative excess of oxygen that could downregulate EPO production. Moreover, dialysis patients in one study maintained the ability to increase EPO production when exposed to high altitude. However, the best example that native kidneys have the potential for restoring EPO production is seen in some patients who developed 12

erythrocytosis after receiving kidney transplants, a situation in which the uremic milieu is eliminated.(9)

2.2.7 Iron deficiency Human iron metabolism is unique because no excretory route exists: it is mostly regulated via uptake. Iron homeostasis depends on iron being absorbed in the duodenum and also recycled from senescent red blood cells. Most of the iron is bound to hemoglobin and is stored in hepatocytes and macrophages of the reticuloendothelial system (Figure 3).

Figure 2. Iron Homeostatis is perturbed in chronic kidney disease http://www.ccjm.org/content/73/3/289.full.pdf+html

Iron is delivered to the maturing erythrocytes by a protein called transferrin, which transports both the iron absorbed and the iron released from macrophages (mainly from recycled senescent red blood cells). Iron homeostasis appears to be altered in chronic kidney disease. 13

For reasons not yet known (perhaps malnutrition), transferring levels in chronic kidney disease are one half to one third of normal levels, diminishing the capacity of the irontransporting system. This situation is then aggravated by the well-known inability to release stored iron from macrophages and hepatocytes in chronic kidney disease. Clinically, diminished iron transport and accumulated iron stores are manifested as low transferrin saturation and elevated serum fer-ritin levels. These characteristics suggest that the interorgan iron transport pathways may be rate limiting factors in erythropoiesis in these patients. Interplay between increased iron losses (as discussed previously) and abnormal interorgan iron transport results in an absolute or functional iron deficiency that can be corrected only by aggressive iron replacement therapy.(10) 2.2.8 Inflammation Interestingly, the anemia of inflammation is also characterized by low serum iron, low transferrin saturation, and impaired release of stored iron, manifested as high serum ferritin. Chronic kidney disease shares several features of the inflammatory state. Elevated circulating levels of inflammatory cytokines such as interleukin have been associated with poor

response to EPO treatment in end-stage renal disease. These cytokines can impair bone marrow function and can significantly alter iron metabolism. The molecular mechanisms involved in the altered interorgan iron communication in both inflammation and chronic kidney disease are yet to be elucidated. Newly discovered molecules have increased our understanding of iron metabo-lism. For example, hepcidin, a 25-amino-acid peptide secreted by the liver, profoundly influ-ences iron metabolism. Recent studies indi-cate that hepcidin inhibits iron absorption, placental iron transfer, and iron release from the reticuloendothelial macrophages, and it mediates the anemia of inflammation.(11) However, hepcidins role in the anemia of chronic kidney disease still needs to be elucidated

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CHAPTER 3 DISCUSSION

Hematopoiesis and the Physiologic Basis of Red Cell Production Before discuss about corelation between chronic kidney disease and anemia, the first we will discuss about what is the role of kidney in hematopoiesis. Hematopoiesis is the process by which the formed elements of the blood are produced. The process is regulated through a series of steps beginning with the pluripotent hematopoietic stem cell. Stem cells are capable of producing red cells, all classes of granulocytes, monocytes, platelets, and the cells of the immune system. For red cell production, erythropoietin (EPO) is the regulatory hormone. EPO is required for the maintenance of committed erythroid progenitor cells that, in the absence of the hormone, undergo programmed cell death (apoptosis). The regulated process of red cell production is erythropoiesis.(12)

Figure 1. The physiologic regulation of red cell production by tissue oxygen tension http://www.harrisonspractice.com/practice/ub/view/Harrison's_Principles_o f_Internal_Medicine_18th_Edition/560057/all/Anemia_and_Polycythemia

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In the bone marrow, the first morphologically recognizable erythroid precursor is the pronormoblast. This cell can undergo 45 cell divisions that result in the production of 1632 mature red cells. With increased EPO production, or the administration of EPO as a drug, early progenitor cell numbers are amplified and, in turn, give rise to increased numbers of erythrocytes. The regulation of EPO production itself is linked to O2 availability.(12) The organ responsible for red cell production is called the erythron. The erythron is a dynamic organ made up of a rapidly proliferating pool of marrow erythroid precursor cells and a large mass of mature circulating red blood cells. The size of the red cell mass reflects the balance of red cell production and destruction. The physiologic basis of red cell production and destruction provides an understanding of the mechanisms that can lead to anemia. The physiologic regulator of red cell production, the glycoprotein hormone EPO, is produced and released by peritubular capillary lining cells within the kidney. These cells are highly specialized epithelial-like cells. A small amount of EPO is produced by hepatocytes. The fundamental stimulus for EPO production is the availability of O2 for tissue metabolic needs. Impaired O2 delivery to the kidney can result from a decreased red cell mass(anemia) , impaired O2 loading of the hemoglobin molecule or a high O2 affinity mutant hemoglobin (hypoxemia), or, rarely, impaired blood flow to the kidney (renal artery stenosis). EPO governs the day-to-day production of red cells, and ambient levels of the hormone can be measured in the plasma by sensitive immunoassaysthe normal level being 1025 U/L. When the hemoglobin concentration falls below 100120 g/L (1012 g/dL), plasma EPO levels increase in proportion to the severity of the anemia. In circulation, EPO has a halfclearance time of 69 h. EPO acts by binding to specific receptors on the surface of marrow erythroid precursors, inducing them to proliferate and to mature. With EPO stimulation, red cell production can increase four- to fivefold within a 1- to 2-week period but only in the presence of adequate nutrients, especially iron. The functional capacity of the erythron, therefore, requires normal renal production of EPO, a functioning erythroid marrow, and an adequate supply of substrates for hemoglobin synthesis. A defect in any of these key components can lead to anemia.(12) Now we know about the role of kidney in hematopoiesis, and if kidney have a problem like chronic kidney disease definitely production of EPO is decreased, in other research found that cytokines is a key point in a inhibition of production of EPO. Erythropoietin regulates erythroid-cell proliferation centrally. Erythropoietin expression is inversely related to tissue oxygenation and hemoglobin levels, and there is a semilogarithmic relation between the erythropoietin response (log) and the degree of anemia (linear). Erythropoietin responses in anemia of chronic disease are inadequate for the degree 16

of anemia in most, but not all, conditions. The cytokines interleukin-1 and TNF- directly inhibit erythropoietin expression in vitro a finding that is probably due, at least in part, to cytokine-mediated formation of reactive oxygen species, which in turn affects the binding affinities of erythropoietin-inducing transcription factors and also damages erythropoietinproducing cells. Although convincing data from human studies are lacking, the injection of lipopolysaccharide into mice results in reduced expression of erythropoietin mRNA in kidneys and decreased levels of circulating erythropoietin. The responsiveness of erythroid progenitor cells to erythropoietin appears to be inversely related to the severity of the underlying chronic disease and the amount of circulating cytokines, since in the presence of high concentrations of interferon- or TNF-, much higher amounts of erythropoietin are required to restore the formation of erythroid colony-forming units.After binding to its receptor, erythropoietin stimulates members of the signal transduction pathways and subsequently activates mitogen and tyrosine kinase

phosphorylation, processes affected by the inflammatory cytokines and the negative-feedback regulation they induce. The response to erythropoietin is further reduced by the inhibitory effects of proinflammatory cytokines toward the proliferation of erythroid progenitor cells, the parallel down-regulation of erythropoietin receptors, and the limited availability of iron to contribute to cell proliferation and hemoglobin synthesis. Finally, increased erythrophagocytosis during inflammation leads to a decreased erythrocyte half-life, along with anticipated damage to erythrocytes that is mediated by cytokines and free radicals.

DIAGNOSIS In chronic kidney disease, anemia may not be entirely attributable to the kidney disease. Anemia of chronic kidney disease should be almost a diagnosis of exclusion after ruling out iron deficiency and nonerythroid cell-line abnormalities. A minimal workup is recommended before starting therapy with an ESA.

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Diagram 2. Anemia workup for patients with chronic kidney disease. http://www.ccjm.org/content/73/3/289.full.pdf+html It should include: A complete blood cell count Red blood cell indices A reticulocyte count Iron measurements (serum iron, total,iron-binding capacity, percent transferrin sat-uration, serum ferritin) Testing for occult blood in the stool. Depending on clinical and laboratory circumstances, a more extensive workup may be indicated, ie: Serum vitamin B12 level Parathyroid hormone level Serum or urine protein electrophoresis A hemolysis panel.(13)

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TREATMENT ESAs should be given to achieve and maintain a target hemoglobin concentration of 11.0 to 12.0 g/dL. There is currently no evidence that raising the hemoglobin to normal levels offers any significant clinical advantage over this target goal.(14) Two ESAs: Epoietin alfa and darbepoetin alfa In the United States, the two agents available for treating anemia in chronic kidney disease are recombinant epoietin alfa (Epogen,Procrit) and darbepoetin alfa (Aranesp). both are effective and safe. Patients on dialysis can receive them intravenously; those not on dialysis can receive them subcutaneously. CKD not on dialysis

Consider initiating ESA treatment only when the hemoglobin level is <10 g/dL and the following considerations apply:

1) The rate of hemoglobin decline indicates the likelihood of requiring a red blood cell transfusion; and

2) Reducing the risk of alloimmunization and/or other red blood cell transfusion-related risks is a goal

If the hemoglobin level exceeds 10 g/dL, reduce or interrupt ESA dose and use the lowest dose sufficient to reduce the need for red blood cell transfusions

Recommended starting dose: 50-100 Units/kg IV/SC 3 times/week CKD on dialysis

Initiate ESA treatment when the hemoglobin level is <10 g/dL If the hemoglobin level approaches or exceeds 11 g/dL, reduce or interrupt the dose of ESA Recommended starting dose: 50-100 Units/kg IV 3 times/week; IV route recommended for patients on hemodialysis

According to the manufacturers, these products differ in pharmacodynamic and pharmacokinetic properties, affinity for the EPO receptor, and half-life. These different characteristics could be used to apply different dosing regimens.(15)

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Iron supplementation
Patients should receive iron supplementation while on ESA therapy, because pharmacologically induced erythropoiesis is limited by the iron supply, as shown by lower ESA requirements after iron supplementation. In addition, as patients make more red blood cells they use up more iron, which can lead to iron deficiency. Serum ferritin and percent transferrin saturation have been shown to drop after 1 week of ESA therapy in both healthy people and iron-replete patients with chronic kidney disease on dialysis. Because patients with kidney disease have altered iron metabolism, their serum ferritin levels and percent transferrin saturation should be maintained at levels higher than in the nor-mal population.16 Recommended maintenance levels for serum ferritin are at least 200 ng/mL; for percent transferrin saturation at least 20%.(16) Most patients with chronic kidney disease need parenteral iron supplementation to achieve the recommended iron levels.2 Possible explanations for the failure of oral iron supplementation include a diminished ability of the oral mucosa to absorb iron and poor patient compliance (due to difficult dosing, side effects, and cost).

Monitoring and controlling side effects Side effects of treatment with ESAs (mainly with recombinant epoietin alfa because it has been studied more thoroughly) include worsening of hypertension and problems at the site of injection. The K/DOQI panel reviewed 47 reports that included a total 3,428 patients. About 23% of patients had a new onset of hypertension or an increase in blood pressure, or both. If hypertension worsens, one should adjust the antihypertensive regimen rather than withhold the ESA treatment.

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CHAPTER 4. CONCLUSSION

Considering that chronic kidney disease is one of the worldwide public health problem and most of its symptoms is caused by anemia, It should be given more attention. The symptoms is asymptomatic especially for patient who is still in chronic kidney stage 1-3. It is extremely important to do minimal work up for patients with chronic kidney disease. It should include a complete blood cell count , red blood cell indices, reticulocyte count, iron measurements (serum iron, total iron binding capacity, percent transferring saturation, serum ferritin), testing for occult blood in the stool. By doing this, we could diagnose patient who having anemia in chronic kidney disease. Moreover it give us indication when the therapy using erythropoiesis stimulating agents (ESAs) should be runned. ESAs are save and should be used for treating patient chronic kidney disease with anemia.

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