CORELATION BETWEEN ANEMIA AND CHRONIC KIDNEY DISEASE

I NYOMAN GDE DANU KUMARA 030.09.115 JAKARTA 2012

CHAPTER I ABSTRACT Anemia is a common comorbidity of chronic kidney disease (CKD). As the diseased kidney loses its ability to produce the erythropoietin essential to the production of hemoglobin, anemia ensues. The age-related rise in CKD makes anemia in CKD a problem of increasing prevalence among residents of long-term care facilities. CKD refers to the entire continuum of renal disease that progresses from mildly impaired kidney function (stage 1, glomerular ltration rate [GFR] _90mL/min/1.73 m2) to signicant deterioration, requiring dialysis or kidney transplant in what is categorized as stage 5 (GFR _15 mL/min/1.73 m2). The denition of anemia is controversial. The WHO denes anemia as hemoglobin < 13 g/dL for men and < 12 g/dL for women. The National Kidney Foundations Kidney Disease Outcomes Quality Initiative, which is the criteria used for Medicare reimbursement, denes anemia in adult men and postmenopausal women as hemoglobin < 12 g/dL, or < 11 g/dL in a premenopausal woman.

CHAPTER II INTRODUCTION

Chronic kidney disease (CKD) is a prevalent, worldwide condition, and the number of patients affected continues to increase. In the United States, it is estimated that, by 2010, > 2 million people will be afflicted with CKD.(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.

CHAPTER III DISCUSSION III.I

Anemia

III.I.I 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.
III.I.II Etiology and Phatogenesis

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.(4) 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, so the iron loss in dialysis patients is 10 to 20 times higher. Therefore, iron supplementation is a mainstay of anemia management.(4) Shortened red blood cell life span The life span of red cells is reduced by approximately one third in hemodialysis patients. 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.(4)

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 1).

Figure 1. Iron Homeostatis is perturbed in chronic kidney disease(3) 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. 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.(5)

Anemia of chronic disease: Any long-term medical condition can lead to anemia. The exact mechanism of this process in unknown, but any long-standing and ongoing medical condition such as a chronic infection or a cancer may cause this type of anemia.

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 hypoxia-inducible 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.(10) 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 erythrocytosis after receiving kidney transplants, a situation in which the uremic milieu is eliminated.(11) Uremic 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 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.(9)

III.I.III DIAGNOSIS ANEMIA IN CHRONIC KIDNEY DISEASE

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.

III.II

Chronic Kidney Disease

III.II.I

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 1 Description Slight kidney damage with normal or GFR* mL/min/1.73m2 More than 90

increased filtration 2 3 4 5 Mild decrease in kidney function Moderate decrease in kidney function Severe decrease in kidney function Kidney failure 60-89 30-59 15-29 Less than 15 (or dialysis)

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

III.II.II 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. 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(1)
III.IV Corelation between Chronic Kidney Disease and Anemia

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.

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 it self is linked to O2 availability.(4) 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.(4) 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 of anemia in most, but not all, conditions.43,44 The cytokines interleukin-1 and TNF- directly inhibit erythropoietin expression in vitro45 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 erythropoietin-producing 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.45 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.46 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.45,47 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 (Table 2).48,49 .

CHAPTER IV CONCLUSION

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 .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. Anemia in chronic kidney disease can occured because the role of cytokines (interferon- or TNF-) to inhibit the kidney to release EPO.

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http://spectrum.diabetesjournals.org/content/21/1/12.full.pdf. 2. American Association of Kidney patient[Internet] Anemia in Chronic Kidney Disease [ update on 2005 December] Available from http://www.aakp.org/aakp-

library/Anemia-in-Chronic-Kidney-Disease/ Accessed on 2012 apr 6 3. Wolters Kluwer Health[internet] Erythropoietin for the anemia of chronic kidney disease in hemodialysis patients[ update on 2012 April 4] Available from http://www.uptodate.com/contents/erythropoietin-for-the-anemia-of-chronic-kidneydisease-in-hemodialysis-patients 4. Tong EM, Nissenson AR. Erythropoietin and anemia. Semin Nephrol 2001; 21:190 203. 5. Goodnough LT, Skikne B, Brugnara C. Erythropoietin, iron, and eryth-ropoiesis. Blood 2000; 96:823833