Anaemia is frequently found in patients with chronic kidney disease and almost universal in End Stage Renal Disease (ESRD) [1]. The prevalence of anaemia is directly related to renal dysfunction and progressively increases when the glomerular filtration rate declines [2]. Anaemia is significantly associated with mortality and morbidity in ESRD patients and it has been linked to the development of left ventricular hypertrophy and cardiovascular disease [3-6].
The pathophysiology of anaemia in ESRD is multifactorial [7]. The proximate cause of the anaemia is relative deficiency of endogenous erythropoietin, a glycoprotein produced by renal tubular cells [8]. Other factors which may cause or contribute anaemia includes iron deficiency, either related to or independent of blood loss from repeated laboratory testing, needle punctures, gastrointestinal bleeding, vitamin B12 and folic acid deficiency, shortened red blood cell survival[9] , severe hyperparathyroidism[10], aluminium toxicity[11], , and hypothyroidism[12].
When untreated, the anaemia of ESRD is associated with a large number of physiological abnormalities, which reduce the quality of life [13] and decreased patient survival [14]. Hence there has been growing focus on improving anaemia management in ESRD.
The introduction of recombinant human erythropoietin (rHuEPO) more than two decades ago revolutionized the treatment of the anaemia in ESRD, having led to a marked reduction in the need for blood transfusion and its attendant complication [15].
Despite the widespread use of rHuEPO, over 50% of the patients do not reach the target haemoglobin levels [1, 16]. Résistance to erythropoietin may occur for several reasons, including inflammation, infection, hyperparathyroidism, and most commonly, iron deficiency [17, 18]. The factors contributing to iron deficiency in ESRD patients are reduced intake, impaired intestinal absorption of dietary iron, blood loses, co-existing chronic inflammation and increased iron needs during treatment with erythropoiesis-stimulating agents (ESA) [19].
Treatment of iron deficiency is an important component of care for patients on haemodialysis. Adequate treatment of iron deficiency is essential to reach target haemoglobin levels and avoid the excessively high rHuEPO doses [20-22]. Therefore effective treatment of anaemia in haemodialysis patients requires ongoing monitoring of iron status.
Monitoring of iron status is important not only to detect iron deficiency, but also to avoid overtreatment in patients who are found to be iron replete. Ideally, the results of iron monitoring should allow for consistent maintenance of the target haemoglobin level, while avoiding excessively high epoetin doses and unnecessary intravenous iron use while allowing these goals to be achieved without excessive cost [23]. Serum ferritin and transferring saturation (TSAT) are the commonly used tests for the assessment of iron status in ESRD [24] because of their widespread availability, extensive literature base, and familiarity. Unfortunately, these tests in ESRD patients are influenced by multiple factors other than total body iron status, most notably inflammation or infection and nutritional status [25]. Hence serum ferritin and TSAT have limited accuracy when used in patients on haemodialysis.
.
AIM
Aim
To find the prevalence of iron deficiency in ESRD patients on haemodialysis.
To evaluate the utility of the current tests- serum ferritin and TSAT, in assessing and monitoring body iron stores.
To correlate the iron status and haemoglobin levels.
REVIEW
OF
LITERATURE
Review of literature
Background and epidemiology
Anaemia contributes significantly to the morbidity and mortality in chronic kidney diseases (CKD) [26]. Erythropoietin stimulating agents (ESA) and supplemental iron are the mainstays of anaemia management in ESRD [27]. The response to ESA therapy is often blunted due to iron deficiency [28], either absolute or functional. Data from National Health and Nutrition Examination Survey (NHANES) demonstrated a cross-sectional prevalence of anaemia in 1.3%, 5.2%, and 44.1% among patients with stage 3, 4, and 5 CKD respectively [29].
Table 1: Stages of Chronic Kidney Disease
Stage
Description
GFR (ml/min/1.73m2 )
1
Kidney Damage with Normal or increased GFR
>90
2
Mild decease in GFR
60-89
3
Moderate decrease in GFR
30-59
4
Severe decrease in GFR
15-29
5
Kidney Failure
<15
BASED ON GUIDELINES OF THE NATIONAL KIDNEY FOUNDATION. K/DOQI CLINICAL PRACTICE GUIDELINES FOR CHRONIC KIDNEY DISEASE: EVALUATION, CLASSIFICATION, AND STRATIFICATION. AM J KIDNEY DIS 2002; 39(2 SUPPL 1):1-266.
The prevalence of iron deficiency in haemodialysis patients has been estimated at 43-90% in various series [17, 30]. Hence the periodical monitoring of iron status plays a pivotal role in the treatment of anaemia in ESRD.
Definition of anaemia
The World Health Organization defines anaemia as haemoglobin (Hb) concentration lower than 13.0 g/dL in men and postmenopausal women and lower than 12.0 g/dL in other women.
The European Best Practice Guidelines for the management of anaemia in patients with chronic kidney disease propose that the lower limit of normal for haemoglobin be 11.5 g/dL in women, 13.5 g/dL in men age 70 and under, and 12.0 g/dL in men older than age 70[31].
The National Kidney Foundation's Kidney Dialysis Outcome Quality Initiative (K/DOQI) recommends a work up for anaemia in patients with chronic kidney disease if haemoglobin level is less than 13.5 g/dL in males and less than 12 g/dL in females[32]
NHANES defined anaemia as haemoglobin less than 12 g/dL in men and less than 11 g/dL in women [33].
Anaemia in ESRD
Anaemia is an almost universal finding in patients with ESRD and its prevalence and severity increase with increasing severity of CKD [27]. The main consequences of renal anaemia include physiological abnormalities, such as decreased blood oxygen content and tissue oxygen tensions and symptoms such as fatigue, reduced exercise capacity, decreased cognition, sexual dysfunction and impaired immunity [34].
In response to anaemia, a number of complex adaptive mechanisms are induced to enable the body to maintain adequate oxygenation. These adaptive mechanisms occur both at organ and cellular level. Adaptive mechanisms to reduced oxygen content include,
Increased cardiac output[35-39]
Reduced peripheral resistance[40]
Increased oxygen extraction from Hb[41]
Altered blood flow both between and within organs[35]
Cellular adaptations[35]
When the capacity of these mechanisms is exhausted, tissue injury occurs. Ironically, the complex pathophysiology of chronic kidney disease alters the adaptations to anaemia in uraemic patients. It includes,
Increased cardiac output induced by anaemia is associated with left ventricular hypertrophy and heart disease.[42-44]
Alteration in endothelial cell function may diminish endothelium induced vasodilatation[45-47], thereby increase the risk of atherosclerosis and impair angiogenesis
CLINICAL CONSEQUENCES OF ANEMIA AND THE IMPACT OF RENAL FAILURE
Inadequately low Epo production
Anaemia Renal failure
Adaptation to low O2 content LV Growth
Decreased BP
Increased cardiac output
Decreased vascular resistance
Potentially Limited
Increased tissue O2 Extraction
Cellular Adaptation
-Metabolism
-Neoangiogenesis
Decreased Tissue pO2
Pathogenic mechanisms for anaemia in ESRD
ESRD patients develop anaemia primarily due to decreased production of red blood cells as a result of a deficiency of the glycoprotein hormone, Erythropoietin [48].
They also develop anaemia on the basis of the following aetiologies [27], like
Iron deficiency
Vitamin B12 and Folic acid deficiency
Bleeding
Shortened red cell survival
Hemolysis
Inherited hemoglobinopathy
Hemolysis
Medications
Malignancy
Bone marrow infiltration
Data from animal models and early human studies demonstrated that anaemia in the setting of reduced kidney function was due primarily to relative erythropoietin deficiency resulting from a loss of endogenous erythropoietin production [49]. This link was confirmed by human studies demonstrating a dramatic improvement in Hb levels with administration of exogenous erythropoietin [50].
Loss of Kidney Parenchyma
Blood Loss:
Diastolic
GI
Phlebotomy
Others
Decreased Erythropoietin Production
Hyperparathyroidism
Erythropoietin/ESA
Hyporesponsiveness
Resistance
Iron Deficiency
Absolute
Functional
ANEMIA
Inflammation /
Infection
Poor Nutrition
Hospitalisation
Retained Uremic Solutes
Erythropoietin
Erythropoietin is a circulating glycoprotein hormone which consists of 165 amino acid peptide chain and 4 carbohydrate chains, 3 linked at the N-terminus and 1 linked at the O-terminus. It is primarily produced by the peritubular interstitial cells of the kidney [51]. Hence the loss of functioning kidney parenchyma results in deficiency of erythropoietin. Under normal conditions, circulating erythropoietin levels are low, but are augmented as much as 100- to 10000-fold in response to anaemia or tissue hypoxia in a process mediated hypoxia-inducible factor 1[52]. But in ESRD patients with reduced functional renal mass, erythropoietin levels are usually inadequate to stimulate erythropoiesis and maintain normal Hb levels.
The erythropoietin receptor is expressed primarily on the surface of erythrocyte precursor cells in the bone marrow [53]. When erythropoietin binds to its receptor, it activates a Janus kinase-2-mediated signal transduction cascade that induces the proliferation of precursor erythroid cells and different into mature erythrocytes [54]. To a lesser extent, erythropoietin receptors are also present on nonhaematopoietic tissues, such as endothelium, heart, brain, and kidney.
Erythropoietin (EPO) is produced when its gene is transcribed, in a process that depends on the binding 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 or 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 [55].
Donnelly [56] proposed that the relative EPO deficiency in chronic kidney disease could be functional response to a decreased glomerular filtration rate. The theory is that the EPO-producing kidney cells may not be hypoxic: if the glomerular filtration rate is low, there is low 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 down-regulate EPO production [56].
Moreover, in one study dialysis patients maintained the ability to increase EPO production when they were exposed to high altitudes [57]. 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 transplant [58].
Recombinant human erythropoietin (rHuEPO)
Introduction of recombinant human erythropoietin (rHuEPO) in late 1980s has made possible partial correction of anaemia in most dialysed patients [59]. The initial clinical trials of rHuEPO showed that 90% of dialysed patients could reach a target haematocrit of 30%. [60] However in actual practice only few patients achieve the target haematocrit level.
Though the efficacy of rHuEPO treatment is impressive, poor responses have been reported [61-63]. Response of dialysis patients to rHuEPO therapy is not homogenous. Some patients require large doses to achieve and maintain adequate haemoglobin level, while others require much less doing so[64]. Therefore various studies have advocated the evaluation of patients with rHuEPO hyporesponsiveness [65-68], but the exact underlying mechanism remains obscure.
The increments of efficient erythropoiesis by rHuEPO are dose dependent over doses ranging between 25 and 500 U/Kg i.v. three times a week in patients with chronic renal failure [59, 69]. Ninety-five percent of the patients will act in response to high doses of rHuEPO, and only 5% of patients exhibit resistance to high doses of rHuEPO without any obvious reasons. The response varies with doses ranging from 120 to 150 U/Kg/Week [69]. This variation remains ambiguous, and several factors could be involved.
Erythropoietin resistance
Definition:
The Best practice guidelines in Europe, indicate erythropoietin resistance when a patient either fails to attain the target Hb concentration while receiving more than 300 IU/kg/week (20 000 IU/week) of Epoetin or 1.5mg/kg of darbepoetin alfa (100mg/ week) [31]. National Kidney Foundation Kidney Disease Outcome Qualitative Initiative (NKF-DOQI) Guidelines determine erythropoietin resistance as a failure to increase the Hb level to greater than 11 g/dL despite an ESA dose equivalent to epoetin greater than 500 IU/kg/wk [32].
Causes:
Iron deficiency is the most frequently encountered cause[21,70,71]] whereas other factors such as infections, chronic inflammations, aluminium toxicity, secondary hyperparathyroidism, bone marrow dysfunction, occult blood loss, hemolysis, and hemoglobinopathy are not uncommon[72]. Other less known factors include age, race, sex, and patients with diabetes mellitus require higher doses of rHuEPO [64].
Role of inflammation:
Inflammation and chronic inflammatory state is an important cause of resistance to erythropoietin treatment. Barany et al showed that inflammation played a major role in ESA resistance. High CRP levels were associated with resistance to erythropoietin treatment. An increase of 80 % in ESA dose was noted in patients with CRP level> 20mg/ml than patients with CRP level<20mg/ml [73].
Occult inflammation is an important factor in ESRD patients without obvious inflammatory source. Periodontal disease has been reported as an occult inflammatory factor. Kadiroglu et al in a study in hemodialysis patients showed that periodontitis can cause hyporesponsiveness to ESA treatment and decrease the haemoglobin levels. After periodontal therapy CRP and ESR level decreased and Hb level increased [74]. Type of dialysis access also has a role. Patients with AV grafts had higher levels of CRP than AV fistulae and subsequently had higher ESA requirements [75]. Uremia perse is proinflammatory state, in which several inflammatory factors are elevated, as the kidney is the major site of elimination of several cytokines [76].
Economic factors
Recombinant human rHuEPO therapy is high-priced and hence its use has been restrained in some countries. The cost of rHuEPO therapy is certainly influenced by hyporesponsiveness to the hormone. Except refractory anaemia associated with bone marrow fibrosis or hemoglobinopathy, most factors leading to poor rHuEPO responses are reversible and remediable. Based on cost effectiveness, it is rational to explore the treatable factors before increasing the doses when confronted with dialysis patients with rHuEPO hyporesponsiveness. By means of early detection and correction of the possible causes, the goals of reducing the rHuEPO dose and decreasing therapeutic efficacy can be achieved [72].
Iron in ESRD Patients
Role of iron
Iron balance in the body
Iron metabolism
Iron deficiency in dialysis patients
Evaluation of iron status in ESRD patients
Role of Iron
Iron is a ubiquitous element which is vital for nearly all living organisms [77]. It can accept and donate electrons willingly, thereby interconverting between ferric (Fe 3+) and ferrous (Fe 2+) states. Based on this capability ,iron plays a key functional role in oxygen-binding molecules like haemoglobin and myoglobin [78] and in various enzymes involved in redox reactions required for production of energy (e.g., cytochromes), the production of metabolic intermediates, and for several host defence enzymes like nicotinamide adenine dinucleotide phosphate [NADPH oxidase].
However, this capability also enables the free ferrous iron to catalyze the production of reactive free radicals that are necessary for the synthesis of adenosine triphosphate (ATP) at the mitochondria level. These free radicals are capable of attacking cellular membranes, proteins and DNA [77]. Under normal conditions, to protect the body from such adverse events, free radicals production is neutralized by antioxidants such as thiol groups, glutathione, vitamin E, etc.[79, 80]. Besides, the iron circulating in the physiologic fluids, is transported across cell membranes and stored, sequestered in proteins such as ferritin and transferrin in both non toxic and readily available forms.Indeed, under normal circumstances, only trace quantities of iron are present outside these physiologic sinks.
EXAMPLES OF FUNCTIONAL IRON CONTAINING PROTEINS IN THE BODY Table 2:
Iron containing protein
Function
Location
Haem Proteins
Haemoglobin
Myoglobin
Oxygen transport
Oxygen storage
Red blood cells, muscles, all tissues
Haem enzymes
Cytochromes a,b,c
Cytochrome c oxidase
Cytochrome P450+b5
Dcytb
Catalase
Peroxidases
Myeloperoxidase
Sulphite oxidase
Tryptophan- 2,3- dioxygenase
Iodase
Electron transfer, transfer of electron to molecular oxygen at end of respiratory chain
Microsomal mixed function oxidases,
phase I biotransformation of xenobiotics,
Ferrireductase.
Hydrogen peroxide breakdown
Peroxide breakdown
Neutrophil bacteriocide
Sulphites to sulphate
Pyridine metabolism
Iodide to iodate
Non-haem iron enzymes
Ribonucleated reductase
Ribonucleotideïƒ 2' deoxyribonucleotides
Synthetic phase of cell division
Iron sulphur proteins
Acotinase
Isocitrate dehydrogenase
Succinate dehydrogenase
NADH dehydrogenase
Aldehyde oxidase
Xanthine oxidase
Phenyl alanine hydroxylase
Tyrosine hydroxylase
Tryptophan hydroxylase
Prolyl hydroxylase
Lysyl hydroxylase
Citric acid cycle and initial steps of oxidative phosphorylation
Aldehydes to carboxylic acid
Hypoxanthine - uric acid
Neurotransmitters, catecholamine and melanin synthesis
Collagen synthesis, both depend upon ascorbic acid
Hence, the lack of iron results in anaemia, ineffective defence mechanism against free radicals, growth arrest etc. Links between iron accumulation and formation of toxic free radicals and progressive tissue damage have been suggested, and an excess of iron (as well as deficiency) may lead to a higher risk of cardiovascular events [81].
Iron balance in the body
ADAPTED FROM: Nancy C Andrews. Disorders of Iron Metabolism. NEJM. 1999C:\Users\Admin\Desktop\iron balance.jpg
The typical total body iron content of adults ranges from 3000 to 4000 mg. The daily iron requirement for erythropoiesis is about 20mg [82]. Iron is usually conserved within the body. Only about 1 to 2mg of iron is lost from the body per day (through blood loss or sloughed mucosal epithelial cells) and it is replaced through diet [78]. Humans strictly conserve iron by recycling it from senescent erythrocytes and from other sources. Such conservation of iron is essential because many human diets contain just enough iron to replace the small losses. However, when dietary iron is more abundant, absorption is appropriately attenuated [82]. Thus, in normal circumstances iron balance is maintained mainly through regulation of iron uptake and recycling from senescent red blood cells.
Iron is delivered to the maturing erythrocytes by a protein called transferrin, which transports both the iron absorbed and iron released from macrophages (mainly from recycled senescent red blood cells [55].
But, iron haemostasis is altered in patients with chronic kidney disease. For reasons yet unknown (perhaps malnutrition), transferrin levels in chronic kidney disease is one half to one third of normal levels, diminishing the capacity of the iron transporting system [83]. This situation is aggravated by the inability to release stored iron from macrophages and hepatocytes in chronic kidney disease [55].
Iron metabolism
Iron distribution in body
Iron absorption
Transport and storage
Effect of rHuEPO on iron me
Iron distribution in body
An adult male approximately has 3 to 4 g of iron in his body (35 to 45 mg/kg) [78, 82]. Body iron is distributed in three pools.
Functional pool
Storage pool
Transport pool
Functional pool
Most of it is in the haemoglobin of circulating red blood cells (65% of the total body iron). About 3-5% of the total body iron is distributed between the myoglobin, haeme enzymes like cytochromes, peroxidases catalases and non-haeme enzymes like ribonucleotide reductase [84].
Storage pool
Storage iron comprises approximately 30% of total body iron. Iron is stored as ferritin and hemosiderin in the reticuloendothelial cells of the liver, spleen, and bone marrow [84].
Transport pool
There is continuous exchange of iron between the storage and the functional pool. Extracellular iron circulates in plasma bound to a specific iron binding protein, namely transferrin (a glycoprotein with mol. wt. 90,000). Approximately 3-4 mg of body iron (comprising 0.1%) is bound to transferrin at any one time. The plasma iron bound to transferrin is constantly exchanged turning over more than ten times in a 24 hrs period [85].
FIGURE 2: Distribution of iron in the body
Iron absorption
Dietary iron is of two types- heme iron and non-heme iron [86]. The main sources of heme iron are the haemoglobin and myoglobin by the consumption of meat, poultry, and fish and that of non-heme iron are cereals, pulses, legumes, fruits, and vegetables. Although the usual absorption of heme iron is approximately 25 % [87], the absorption of heme iron increases to about 40% during iron deficiency and about 10 % during iron repletion [88]. Non-heme iron is the major part of dietary iron. The non-heme iron absorption is influenced by the iron status of the individual and by various factors in the diet. Calcium has a negative influence on the absorption of heme iron and to the similar extent it also influences non-heme iron [89].
Dietary iron mostly exists in ferric form (Fe3+), bound to proteins or organic acids. Dietary ferric form is converted to the ferrous form in the stomach. This reduction is greatly promoted by the presence of low gastric pH and dietary ascorbic acid [90, 91]. The advantage of conversion is that the ferrous form (when compared to ferric form) is more readily released from the bound organic ligands.
Table 3: ABSORPTION OF IRON
HEME IRON ABSORPTION:
Iron status of the person
Amount of dietary heme iron
Presence of calcium in meal
NON-HEME IRON ABSORPTION:
Iron status of the person
Amount of potentially available non-heme iron
( adjustment for iron fortification and iron contamination)
*Balance between enhancing and inhibitory factors
Enhancing factors
Ascorbic acid (eg: certain fruit juices, potatoes..), meat, chicken, fish, fermented vegetables (eg: sauerkraut), fermented soy sauces.
Inhibiting factors
Phytates and inositol phosphates, iron binding phenolic compounds
Inhibition of iron absorption
Phytates are found in all kinds of grains, vegetables, roots (e.g., potatoes), nuts and fruits. Phytates are inositol hexaphosphate salts. They are the storage form of phosphates and minerals. Phytates hinder iron absorption in a dose-dependent manner and even minimal amounts of phytates have a distinct effect [92].
Bran strongly inhibits iron absorption since it has high content of phytate. Oats also inhibit iron absorption because of their high phytate content that results when native phytase in oats is destroyed during the heating process done to avoid rancidity [93]. Consumption of adequate amounts of ascorbic acid can neutralize this inhibition [94]. Non-phytate-containing dietary fibre component does not influence the absorption of iron.
Most plants have phenolic compounds in them as part of their defence system. Few of the phenolic compounds, particularly those with galloyl groups are responsible for the inhibition of iron absorption [95]. Coffee, tea, and cocoa are certain plant products that have iron-binding polyphenols [96]. Several vegetables, particularly green leafy vegetables (e.g., spinach), herbs and spices contain considerable amounts of galloyl groups which hinder iron absorption. Betel leaves consumption (common in India) has negative influence on absorption of iron.
Calcium present in salt or in dairy products significantly inhibit the absorption of both heme and non-heme iron [89]. This competition is overcome by increased iron intake, thereby increase its bio-availability and avoiding simultaneous intake of calcium rich foods and foods rich in iron [97]
Enhancement of iron absorption
Ascorbic acid, both synthetic and native forms, is the strong stimulator of non-heme iron absorption [91]. Meat, fish, and seafood all enhance the absorption of non-heme iron. Meat enhances iron nutrition by promoting the absorption of both heme and non-heme iron and itself being the source of the well-absorbed heme iron. Epidemiologically, the intake of meat was found to be associated with a lower prevalence of iron deficiency [87]. In certain studies, Organic acids like citric acid was found to increase the absorption of non-heme iron [92].
Regulation of iron absorption
The intestinal absorption of iron is regulated in several ways. First, it is modulated by the amount of iron consumed in the diet. This mechanism is referred to as the dietary regulator. Many days after bolus of dietary iron, absorptive enterocytes become resistant to acquire extra iron. The phenomenon is called mucosal block [98]. It occurs probably due to accumulation of intracellular iron which makes the enterocyte to believe that it has met the set-point requirements. This can occur even during systemic iron deficiency. A second regulatory mechanism is store regulator that responds mainly to total body iron [99]. It can also influence the amount of iron absorbed to a certain extent: iron absorption is modulated by a factor of only two to three in iron deficient states as compared with iron-replete states [100]. The molecular basis of the stores regulator is not known. Most likely it acts in response to the saturation of plasma transferrin with iron, at the level of crypt-cell programming. Animal experiments have proposed that the levels of the apical transporter (DMT1) are altered secondary to changes in body iron stores [101]. The third mechanism is the erythropoietic regulator [99], which is not influenced by the iron levels at all. But, it modulates iron absorption secondary to the needs for erythropoiesis. The erythropoietic regulator has a more capability to increase iron absorption than the stores regulator. The erythropoietic regulator mostly involves a soluble signal which is carried by plasma from the bone marrow to the intestine [78].
Mechanism of absorption and transport
The absorption of dietary iron, both haem and non haem form, occurs in the mature villus enterocytes of the duodenum and proximal jejunum. The initial step in the absorption process is the iron uptake from the luminal part of the intestine through the apical membrane into the enterocyte. This step is mediated by divalent metal transporter 1(DMT 1), the brush border iron transporter [102].
DMT 1(also known as SLC11A2) is a solute carrier group of membrane transport proteins. It transfers iron in ferrous form across the apical membrane and into the enterocyte [103]. DMT1 is not a specific transporter for iron. It transports many divalent metal ions such as copper, manganese, cobalt, zinc, cadmium, and lead. DMT1 is active in a low pH environment (as in duodenum) because it requires proton co-transporter [104].
ADAPTED FROM: Adriana Donovan, Cindy N, Roy, Nancy C Andrews. The ins and outs of iron homeostasis. Physiology. 2006; 21: 115-123.
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Most of the iron in the diet which enters the lumen of the duodenum is in the oxidized or ferric form. Hence it must be reduced before it is taken up by enterocytes. The reduction of iron occurs enzymatically, likely by duodenal cytochrome b (Dcytb) which is a brush border ferric reductase [102].
Dietary haem is also be transported across the apical membrane by a haem carrier protein 1(HCP 1) subsequently metabolized in the enterocytes by haem oxygenase 1(HO-1) to liberate Fe2+ [104].
Both directly internalized and haem-derived ferrous iron is processed by the enterocytes and eventually transported across the basolateral membrane into the bloodstream by the Fe2+ transport protein ferroportin (also known as SLC11A3) [103]. Ferroportin also plays a key role in the export of iron from other cell types, such as macrophages into the circulation [105].
The ferroportin-mediated efflux of Fe2+ is coupled by its re-oxidation to Fe3+. It is catalysed by the membrane-bound ferroxidase hephaestin which physically interacts with ferroportin. Iron which is not transported to the bloodstream is integrated into the iron storage molecule, ferritin and is lost when the cell gets sloughed at the villus tip [102].
The iron absorption by enterocytes is influenced by several factors such as body iron stores variations, changes in the rate of erythropoiesis, hypoxia and inflammation. These factors effect changes in the duodenal expression of the major enterocyte iron transport molecules, mainly DMT1, Dcytb, and ferroportin 1, at the mRNA and protein level [102].
The absorbed iron is scavenged by transferrin and it maintains Fe3+in a redox-inert state and delivers it into tissues. The iron that is bound to transferrin is highly dynamic. It undergoes a turnover of more than ten times daily to maintain erythropoiesis. The transferrin iron pool is replenished mainly by iron recycled from effete erythrocytes and only to a lesser extent by dietary iron absorption iron. Senescent erythrocytes are sequestered by the reticuloendothelial macrophages and it metabolizes haemoglobin to release the iron into the circulation [103].
In analogy to intestinal enterocytes, the macrophages export Fe2+ from their plasma membrane to the bloodstream via ferroportin. This step is coupled by re-oxidation of Fe2+ to Fe3+ by ceruloplasmin and followed by the binding of Fe3+to transferrin. Thus ferroportin plays a primary role in the release of iron from tissues into the circulation [103].
Storage of iron
Iron is stored in the body either as ferritin or as hemosiderin. The former is water-soluble; the latter is water-insoluble [85]. Ferritin is composed of a core ferrihydrite crystal (Fe2O3 · 9 H 2O) x within an apoferritin shell [106]. Most of the storage iron is in the form of ferritin, approximately 65%. Liver is the major site of ferritin storage. Spleen, bone marrow, and reticuloendothelial macrophages are also sites of ferritin storage.
Hemosiderin occurs predominantly in macrophages of the monocyte-macrophage system (marrow, liver, and spleen). Hemosiderin contains approximately 25 to 30 % of iron by weight. Under pathologic conditions, it may accumulate in large quantities in almost every tissue of the body. Hemosiderin consists of aggregates of ferrihydrite core crystals, largely devoid of apoferritin. Depletion of the storage iron occurs when iron loss exceeds iron absorption [85].
The mobilization of storage iron involves the reduction of Fe3+ to Fe2+, its release from the core crystal and its diffusion out of the apoferritin shell. As it passes from cytosol to plasma, it must be reoxidized, either by hephaestin in the cell membrane or by ceruloplasmin in plasma, before it binds to transferrin [85].
Role of Hepcidin
The liver plays a key role in the regulation of intestinal iron absorption. Though it has known that the liver is the chief storage site of excess iron, the direct role of liver in regulating iron absorption was only apparent after discovery of the iron regulatory hormone hepcidin [107]. It is secreted by hepatocytes into the circulation. It acts as an inhibitor for iron absorption and release of iron from macrophages and other cell types. The hepcidin production is decreased by stimuli which increases iron absorption (e.g., increased erythropoiesis and iron deï¬ciency) and increased by the conditions where absorption is decreased (e.g., iron loading and inflammation) [82,108].
Hepcidin inhibits intestinal iron absorption as well as the release of iron from macrophages. The first occurs via the DMT 1, the later is based on internalisation and degradation of iron exporter ferroportin [19]. This hormonal regulation of iron efflux from cells via the hepcidin/ferroportin axis is of paramount importance for systemic iron homoeostasis [103]. Uremia is a state of heightened inflammatory activation, and increased hepcidin production under this condition may explain iron deficiency in the majority of patients with ESRD.
http://ahdc.vet.cornell.edu/clinpath/modules/chem/images/hepcidin.jpg
Iron deficiency in dialysis patients
An important factor in many anaemic patients with ESRD is iron deficiency. There is a spectrum of iron deficiency which occurs in ESRD patients with anaemia; particularly when they are treated with erythropoietin agents because these agents stimulate the bone marrow to a supraphysiological rate of red blood cell production. Hence, the normal rate of iron delivery to the bone marrow becomes insufficient to meet the iron demands of the erythropoietin stimulated marrow [25].
Forms of Iron deficiency:
Iron deficiency can be categorized as absolute or functional.
Absolute iron deficiency is defined by the reduction in the bone marrow reticuloendothelial iron. Clinically absolute iron deficiency results from a combination of iron utilization in response to ESA therapy, impaired gastrointestinal absorption, and blood loss (thereby iron loss) via the dialytic circuit, access surgery/intervention, and frequent phlebotomy [27]. In clinical practice absolute iron deficiency is determined by a ferritin level of less than 200ng/ml and transferrin saturation (TSAT) of less than 20% [109].
Functional iron deficiency is defined by the presence of adequate bone marrow iron stores, but an impaired ability to mobilize these stores for erythropoiesis. It is typically diagnosed when the TSAT is less than 20% but serum ferritin is normal or elevated [27]. Functional iron deficiency results from greater iron need for haemoglobin synthesis stimulated by erythropoietic factor. This process can overwhelm the rate of release of iron from iron stores and cause functional iron deficiency [64].
Pathogenesis of Iron deficiency in dialysis patients:
ESRD patients on rHuEPO treatment consequently have an increased demand for iron as erythropoiesis is stimulated in them .But there are three key mechanisms that are proposed to explain the increased frequency of iron deficiency. They are abnormal iron absorption, external blood loss, and functional iron deficiency [110].
1. Iron absorption in dialysis patients:
Iron absorption from gastrointestinal tract is influenced by the level of body iron stores, erythropoietin therapy, and the extent of erythropoiesis. Even among individuals with normal renal function, only a minimal proportion of ingested iron is absorbed (about 1% to 2% of ingested iron absorbed daily). But earlier reports have shown that iron absorption usually increases in the presence of accelerated erythropoiesis or iron deficiency [111,112].
Conflicting data are noted on literature regarding iron absorption in dialysis patients [111-115]. Studies in the pre-rHuEPO era tend to confirm that iron absorption was normal in dialysis patients [114, 115]. However studies conducted in rHuEPO treated patients show that there is a marked reduction in intestinal iron absorption [111, 115]. In a study by kooistra et al [111], classic ferrokinetic techniques were used to show that mucosal uptake and iron retention were subsequently decreased in both iron-replete and iron deficient haemodialysis patients. In iron deficient non-uraemic patients, mucosal uptake and iron retention were 86% and 81% respectively. In iron deficient haemodialysis patients, in contrast, mucosal uptake was 48% and iron retention was 36% only. The higher ferritin levels, which occur in dialysis patients despite low iron stores, may also impair the normal feedback that would increase absorption during deficiency states [84].
2. External blood loss:
There are many factors which contribute to the ongoing blood loss among dialysis patients. It includes [111],
Blood retention by the haemodialysis filter and tubings.
Frequent blood sampling for laboratory testing.
Accidental blood loss from the haemodialysis access
Occult gastro-intestinal bleeding
Akmal et al [117] showed that significant amount of iron (1 to 3 g of iron annually) are lost through the above causes. It should be noted that the higher the haematocrit achieved with erythropoietin therapy, the larger is the iron loss with each millilitre of lost blood, since more erythrocytes containing iron are lost at a raised haematocrit [110]. The Anaemia work Group of the Dialysis Outcome Quality Initiative had suggested that 25 to 100 mg of iron must be replaced weekly in haemodialysis patients to compensate for the iron lost due to ongoing external blood losses [112].
3. Functional iron deficiency:
The complicating feature in the management of iron deficiency in the dialysis population is the concept of functional iron deficiency [69]. In this abnormality, the iron is present in sufficient quantity in storage tissues but there is a problem in its utilisation. Hence the erythroid precursor cells are unable to efficiently access the iron [117]. Firstly, this may be because of supra-physiological rate of erythropoiesis which occurs during rHuEPO therapy, which may lead to increased available iron demand, to outstrip its supply even when storage iron is adequate. Secondly, there may be some reticulo-endothelial (RE) blockade which may limit access to body's iron supply. The defective release of iron from reticuloendothelial cells could be responsible for the ineffective erythropoietin therapy in a significant number of patients [118].
This reticuloendothelial blockade commonly occurs in the setting of acute or chronic inflammation/infection and correlates with a high C-reactive protein and/or a high erythrocyte sedimentation rate. It is known that in various chronic diseases the increased cytokine production causes macrophage of the reticuloendothelial system to increase their uptake of iron. Hence, due to the of the inflammatory state and likely mediated by the regulatory hormone , hepcidin (Fig ), the iron that is stored in RE storage gets "locked up" there and is not released to transferrin. Therefore, transferrin-bound iron, which is reflected by TSAT, is low despite a normal or elevated ferritin [25].
Therefore functional iron deficiency exhibits defective iron mobilization/utilization that cannot keep pace with the demands for the accelerated erythropoiesis. In clinical practice, functional iron deficiency is assessed by the response to a course of parenteral iron producing either a decrease in the dose of rHuEPO needed to maintain the target haematocrit or increase in haemoglobin at the same dose of epoetin [70, 119-122].
Evaluation of iron status in ESRD patients
Treatment of iron deficiency is of paramount importance for patients on haemodialysis. When iron deficiency is not promptly recognized and adequately treated it leads to sub-optimized anaemia therapy. This leads to difficulty in reaching target haematocrit or haemoglobin levels or the need for excessively high epoetin doses [20-22].
Hence the diagnostic tests for iron deficiency must be performed on a regular basis, i.e. Every three months for patients on stable rHuEPO therapy and every month during initial rHuEPO therapy [32]. Testing is important not only to detect iron deficiency, but additionally to avoid overtreatment in those who are iron replete [23]. Overtreatment with intravenous iron can cause iron associated risks, including anaphylaxis, hemosiderosis, hepatic dysfunction and cardiovascular and infectious morbidities [123].
Tests for evaluation of iron status in patients with ESRD
Tests to assess the iron status in ESRD patients must be a guide to iron therapy and help clinicians to optimize iron availability and minimize iron toxicity. Ideally the results of iron monitoring should allow for consistent maintenance of the target haemoglobin level, while avoiding excessive high epoetin doses [23].
Many tests have been evaluated for the diagnosis of iron deficiency in patients with ESRD. The different tests approach the problem from three separate perspectives. Firstly for evaluation of storage iron in body stores serum ferritin and bone marrow specimens stained for iron are used. Secondly for evaluation of readily available iron the tests employed are serum iron, total iron binding capacity and transferrin saturation (TSAT). Third and finally the effect of iron status on red blood cells is reflected by the mean cell volume (MCV), red cell ferritin, mean cell haemoglobin concentration (MCHC), the percentage of hypochromic red cells and the zinc protoporphyrin concentration.
Tests assessing the iron status in ESRD population in general use are serum ferritin and transferrin saturation [24, 25, 32]. Reticulocyte haemoglobin content (CHr) is lately used as a marker of iron status and early predictor of response to iron therapy in haemodialysis patients [23, 25]. Other parameters in use include percentage of hypochromic red cells, soluble transferrin receptor, and hepcidin. But these parameters lack robust evidence, availability, and require future studies [32].
Serum Ferritin:
Although a significant proportion of iron stored in the reticulo-endothelial system is present as ferritin, only trace quantities of ferritin (devoid of iron) enter the circulation. Nonetheless the serum ferritin concentration is proportional to total body iron stores, with the lower limit of normal ranging from 8-30 ng/ml [124]. Levels below this range are highly predictive of iron deficiency. In non-uraemic population, the serum ferritin has been considered to be the most valuable diagnostic test for iron deficiency [125]
However, there are few limitations to the diagnostic value of serum ferritin for iron deficiency in patients with ESRD. In many conditions associated with inflammation such as infections, rheumatoid arthritis, malignancy, smoking, and chronic renal disease, the serum ferritin concentration increases independent of iron stores [126]. Secondly patients with liver disease also have an elevated serum ferritin level probably because of release of intracellular ferritin by hepatocytes [127]. More so the presence of occult inflammation in chronic renal failure may increase the serum ferritin level to higher than expected levels.
Another problem in the use of serum ferritin in ESRD patients is that it measures iron present in the body iron storage pool. Therefore in patients with ESRD there is a tendency for iron to be sequestrated in the storage pool, with decreased availability for erythropoiesis. In such patients, serum ferritin concentration underestimates the actual iron needs.
After the introduction rHuEPO into the clinical use, it was estimated that the lower limit of normal for the serum ferritin in patients with ESRD should be 100ng/ml [59]. In 1991, Allegra et al [128 ] studied 72 haemodialysis patients and concluded that a serum ferritin above 191ng/ml essentially excluded a diagnosis of iron deficiency. In contrast Barth et al [129] found that a serum ferritin as high as 600ng/ml, some haemodialysis patients may still be relatively deficient of iron.
Trang et al [71] found that a serum ferritin level of 300ng/ml had 100% ability to separate patients with or without initial resistance to rHuEPO. Below a level of 300ng/ml, however, the serum ferritin level was not predictive of which patients responded to intravenous iron therapy with an improvement in erythropoiesis.
Kalantar-Zadeh et al [130] performed bone marrow studies in haemodialysis patients and found no level of serum ferritin with sufficient accuracy for predicting the presence of iron stores.
Fishbane et al [110] also found no level of serum ferritin that had an optimal combination sensitivity and specificity. Their study used a functional approach administrating a surplus of intravenous iron and evaluating the erythropoietic response. At a value of 100ng/ml, the serum ferritin lacked sensitivity (48%). The sensitivity was maximal at 90%., using a value of 300ng/ml as the cut off, but with significant decrease in specificity. The only level with marginal utility was at 150 ng/ml with a sensitivity of 71% and specificity of 69%. The National Kidney Foundation Kidney Disease Outcome Quality Initiative (NKF KDOQI) guidelines recommended a target ferritin level greater than 200 ng/mL [32].
In the literature, most studies have shown that serum ferritin correlated very well with bone marrow iron stores and remain the best single indicator of iron status [131-135]. The occasional lack of correlation [136] is probably due to increase in serum ferritin with inflammation, or as an acute phase reactant. In other studies also, serum ferritin levels have been found to correlate well with mobilize iron stores and semi-quantitative assessment of stainable marrow iron in normal subjects [124, 137].
Transferrin saturation (TSAT)
TSAT is the ratio of serum iron to total serum iron binding capacity. It is a measure of circulating iron and is 15% or less (normal values 16 to 40%) in patients with iron deficiency [19]. Transferrin saturation along with serum ferritin is the two most frequently used test for evaluation of iron status in CRF.
It is calculated as the serum iron concentration divided by the total iron binding capacity, with result multiplied by 100. The numerator of the equation, i.e. serum iron concentration, quantitates iron in circulation bound to transferrin. In theory, it is the most direct measure of iron available for erythropoiesis. However, its practical utility is limited by inter laboratory variability. The denominator TIBC is an indirect measure of circulating transferrin [TIBC (ïg/dl) = Transferrin (mg/dl) X 1.4]. The TIBC increases in patients with iron deficiency [138].
Transferrin saturation fluctuates widely due to a diurnal variation in serum iron [139] and transferrin affected by the nutritional status. TSAT decreases if acute or chronic inflammation co-exists, indicating functional iron deficiency in patients with CKD. Functional iron deficiency is defined as TSAT <20% and normal or elevated serum ferritin levels [19].
Traditionally, a TSAT of <20% in haemodialysis patients has been considered to be indicative of iron deficiency. However several studies [71,121,135,140,141] have demonstrated that a TSAT of < 20% versus >20% is not an accurate discriminator between patient who are and are not iron deficient. Although a vast majority of patients who have a TSAT <20% are iron deficient, there are some patients who have an TSAT >20% who are able to achieve a Hct of 33% to36% and/or do not respond to higher doses of iron (and TSAT levels) with either an increase in Hct or maintenance of Hct with a reduced dose of epoetin. However there are also many patients who have a TSAT >20%, who are functionally iron deficient (i.e. they respond to higher doses of iron, and a corresponding increase in their TSAT, with either an increase in their Hct or maintenance of their Hct at reduced dose of epoetin[71,121,135,140,141]]. Also certain reports have stated that a transferrin saturation of <20% indicates absolute or functional iron deficiency in this population [120,142]. Several clinical studies have attempted to validate this recommendation.
Kalantar-Zadeh et al [130] found that a transferrin saturation of<20% had a sensitivity of 88% but a specificity of only 63%. Interestingly if patients with hypoproteinemia were excluded, the sensitivity of the test increased to 100% and specificity to 80%
Similar results were found in another study group. At a TSAT of <21%, the sensitivity and specificity for the diagnosis of iron deficiency were 81% and 63% respectively. The specificity increased to 88% if the cut off for TSAT was lowered to 15%, but with reduction in sensitivity to 16%. In contrast the sensitivity could be maximised (92%) by increasing the cut off to 27% to 30% but with the significant drop off in specificity (22%)[135]. The NKF KDOQI recommended treatment target of TSAT is 20% [32].
Reticulocyte haemoglobin content (CHr)
CHr has been recommended as an alternative marker of iron status and as an early predictor of response to iron therapy in haemodialysis patients [143,144]. The test was initially reviewed in depth by Brugnara and colleagues [145]. The CHr test is a direct measure of iron sufficiency at the level of the reticulocytes, the first circulating form of erythrocytes [145,146]. Because reticulocytes exist in circulation approximately for only a day, CHr provides a snapshot of the iron directly available for haemoglobin synthesis and is an early indicator of the body's iron status [23].
The test has been studied in haemodialysis patients, and various reports have been published so far. Fishbane et al [143] evaluated CHr in 32 haemodialysis patients and found the sensitivity and specificity to detect iron deficiency was 100% and 80% respectively. Mittman et al [144] evaluated CHr in 364 haemodialysis patients receiving rHuEPO and found it to be a predictor of functional iron deficiency. Likewise, Bhandari et al[147] studied 22 haemodialysis patients with initial serum ferritin <60ng/mL and founded that CHr increased after intravenous iron treatment. It was concluded that CHr is useful tool to identify functional iron deficiency. According to Fishbane et al [23], a CHr< 29 pg as measured by a Technikon H*3 blood analyser indicates the presence of iron deficient erythropoiesis. Tsuchiya et al studies also confirmed CHr is a reliable tool to diagnose iron deficiency. He reported that iron deficient erythropoiesis was present in haemodialysis patients at CHr<32 pg, measured by the AD-VIA-120 system. Brugnara et al [148] demonstrated with a CHr cutoff level of 27.2pg, iron deficiency can be diagnosed with a sensitivity of 93.3% and a specificity of 83.2%. NKF DOQI recommends a target of CHr greater than 29pg/cell [32].
Other iron status tests that are studied include zinc protoporphyrin, percentage of hypochromic red blood cells, and soluble transferrin receptors. Datas to support these tests as targets for iron treatment is poor or unavailable [32].
METHODOLOGY
METHODOLOGY
Study place
The study was conducted in PSG Hospitals, Coimbatore.
Study period
The study was conducted during the time period of October 2010 to December 2011. Study population
Patients diagnosed with end stage renal disease on regular haemodialysis for a time period of 3 months or more were included in the study after application of inclusion and exclusion criteria.
Inclusion criteria
ESRD patients on haemodialysis for a time period of 3 months or more were selected. ESRD due to all etiologies were included.
Exclusion criteria
Age less than 18 yrs
Evidence of acute infection or trauma in last 4 weeks
Recent bleeding episodes
Blood transfusion in the last one month
Malignancy
Post-Transplant status
Liver disease
Chronic infections
Haemoglobinopathies
Other Haematological diseases
Study method
The study was conducted among the ESRD patients undergoing haemodialysis in department of nephrology in PSG hospital. All ESRD patients on haemodialysis for at least 3 months were taken up for the study after the application of the inclusion and exclusion criteria and after obtaining consent. The study protocol was approved by the institute's Ethics committee. The enrolled patients were divided into two groups - those who receive rHuEPO and those not on rHuEPO therapies.
The diagnostic biochemical tests that were used to assess the iron status include serum ferritin and TSAT {calculated from serum iron and total iron binding capacity (TIBC)}.
Patients were categorized to have normal, deficient, indeterminate, or overload status based on the values of TSAT and serum ferritin. Based on NKF-DOQI guidelines, iron deficiency was defined as serum ferritin <200mg/dl and TSAT <20%, while iron overload as serum ferritin > 500 mg/dl and TSAT > 50%. Patients who had values between these limits were categorized to have normal iron status, whereas those not conforming to any of these groups were categorized as indeterminate.
The utility of these two indices to diagnose iron status was calculated by number of patients diagnosed of their iron status divided by total number of patients and was expressed as a percentage.
The haemoglobin level of all the enrolled patients was also tested. The Correlation between iron status {Serum Ferritin and TSAT} and haemoglobin level was assessed among the study population.
OBSERVATION
AND
RESULTS
Observation
Demographic Data:
Number of patients:
100 patients were included in the study after the fulfilment of both the inclusion and exclusion criteria.
Gender:
FREQUENCY
PERCENT
Male
63
63.0
Female
37
37.0
Total
100
100.0
Age of the study population:
AGE IN YEARS
FREQUENCY
PERCENTAGE (%)
18yrs- 20 yrs
1
1.0
21yrs - 40 yrs
25
25.0
41yrs - 60 yrs
54
54.0
More than 60 yrs
20
20.0
Total
100
100.0
Duration of Haemodialysis:
Duration in years
Frequency
Percent
Less than 1yr
50
50.0
1 - 3 yrs
34
34.0
3 - 5 yrs
12
12.0
More than 5yrs
4
4.0
Total
100
100.0
Co-morbidities:
CORMORBITIES
NO OF PATIENTS
Hypertension (HT)
86
Diabetes Mellitus(DM)
28
Coronary artery disease(CAD)
16
Pulmonary Arterial Hypertension (PAH)
14
Left Ventricular failure(LVF)
14
Mitral Regurgitation(MR)
8
Diastolic Dysfunction
3
Hypothyroidism
3
Tricuspid regurgitation(TR)
2
Old Pulmonary Tuberculosis (TB)
2
Asthma
1
Biventricular dysfunction
1
Chronic Deep Vein Thrombosis(DVT)
1
GBS recovered
1
Old CerebroVascular Accident (CVA)
1
Dyslipidemia
1
Chronic obstructive pulmonary disease (COPD)
1
Aortic regurgitation(AR)
1
Mitral stenosis (MS)
1
Seizure disorder
1
Erythropoietin treatment:
FREQUENCY
PERCENT
Patients on Erythropoietin
65
65.0
Patients not on Erythropoietin
35
35.0
Total
100
100.0
Iron Supplementation:
FREQUENCY
PERCENT
Oral
56
56.0
IV 100 mg
44
44.0
Total
100
100.0
RESULTS
100 ESRD patients were studied for iron status using serum ferritin and TSAT
26% of patients had absolute iron deficiency
72% of patients were diagnosed of their iron status and the remaining 28 % patients' iron statuses were indeterminate.
Diagnosed:
IRON STATUS
No. OF PATIENTS
PERCENTAGE
(%)
TSAT
(m+/-sd)
(%)
S.FERRITIN
(m+/-sd)
ng/ml
Diagnosed:
Adequate
Deficient
Overload
72
43
26
3
72
43
26
3
Indeterminate state:
IRON STATUS
No. of PATIENTS
PERCENTAGE
(%)
TSAT
(m+/-sd)
S.FERRITIN
(m+/-sd)
ng/ml
Indeterminate status:
High serum ferritin-low TSAT (functional iron deficiency)
Low serum ferritin-high TSAT
28
17
11
28
17
11
Iron status in ESRD patients on Erythropoietin
IRON STATUS
NO OF PATIENTS
PERCENTAGE
TSAT
(M ± SD)
SERUM FERRITIN
(M ± SD)
Diagnosed
Adequate
Deficiency
Overload
48
32
14
2
74%
49.23%
21.54%
3.08%
28.78 ± 9.37
14.98 ± 4.03
56.25 ± 2.95
553.72 ± 315.21
105.57 ± 45.78
1451.00± 776.40
Indeterminate
High Feritin, Low TSAT
Low Ferritin, High TSAT
17
9
8
26%
14%
12%
19.54 ± 5.58
307.35 ± 213.35
Iron status in ESRD patients not on Erythropoetin:
IRON STATUS
NO OF PATIENTS
PERCENTAGE
TSAT
(M ± SD)
SERUM FERRITIN
(M ± SD)
Diagnosed
Adequate
Deficiency
Overload
24
11
12
1
69%
31.4%
34.5%
2.9%
31.87 ± 8.83
14.35 ± 4.27
71.32 ± Nil
674.36 ± 524.46
123.58 ± 49.60
1436 ± nil
Indeterminate
High Feritin, Low TSAT
Low Ferritin, High TSAT
11
8
3
31%
23%
9%
20.46 ± 6.37
413.73 ± 263.14
Multiple regressions between Diagnosed and Haemoglobin:
WOMEN
MEN
Difference
P
Difference
P
Adequate
Reference
