Avalaible i.v. iron preparations. *: www.globalrph.com - **: www.medicines.org.uk
\r\n\tIt is believed that deterioration in structures are needed to be linked with risk management in construction. Faulty of construction directly affect to the deterioration. Therefore, second part of this book considers the lessons learned in construction management. Project and site managers, quality engineers are most welcome to discuss the reasons of deteriorated structures through project planning to the serviceability of such structures.
",isbn:null,printIsbn:null,pdfIsbn:null,doi:null,price:0,priceEur:null,priceUsd:null,slug:null,numberOfPages:0,isOpenForSubmission:!1,hash:"c25011195dc649bb9b63d88c55c2f706",bookSignature:"Dr. Hakan Yalciner",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/7450.jpg",keywords:"Structures, deterioration, seismic performance,monitoring techniques, serviceability of structures,repair and strengthening methods, scoring of structures, material degradation, environmental effects, time dependent effects, risk management, lessons learned, construction management",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfDimensionsCitations:0,numberOfTotalCitations:0,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"March 27th 2018",dateEndSecondStepPublish:"April 17th 2018",dateEndThirdStepPublish:"June 16th 2018",dateEndFourthStepPublish:"September 4th 2018",dateEndFifthStepPublish:"November 3rd 2018",remainingDaysToSecondStep:"3 years",secondStepPassed:!0,currentStepOfPublishingProcess:5,editedByType:null,kuFlag:!1,biosketch:null,coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"72283",title:"Dr.",name:"Dr. Hakan",middleName:null,surname:"Yalciner",slug:"dr.-hakan-yalciner",fullName:"Dr. Hakan Yalciner",profilePictureURL:"https://mts.intechopen.com/storage/users/72283/images/system/72283.jpeg",biography:"Associate Professor Dr. Hakan Yalciner is an earthquake and structure engineer in Erzincan Binali Yıldırım University and chair in the Department of Civil Engineering. Dr. Hakan Yalciner received his PhD from Eastern Mediterranean University. He is a voting member of ACI Committees 546-00 (Repair of Concrete) and 546-0E (Corrosion Studies). His research interests include performance analysis of structures under extreme conditions and loads, such as corrosion, seismic events, and blast. Dr. Yalciner developed different empirical models for the prediction of the structural behavior of corroded reinforced concrete members. He is currently director of the 13th March of Structural Mechanics Laboratory in Erzincan Binali Yıldırım University. His total accepted budget for academic projects in 2018 was US$250,000.\nwebsite: https://drhakanofficials.info/",institutionString:"Erzincan University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"Erzincan University",institutionURL:null,country:{name:"Turkey"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"11",title:"Engineering",slug:"engineering"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"247041",firstName:"Dolores",lastName:"Kuzelj",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/247041/images/7108_n.jpg",email:"dolores@intechopen.com",biography:"As an Author Service Manager my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review, to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. Whether that be identifying an exceptional author and proposing an editorship collaboration, or contacting researchers who would like the opportunity to work with IntechOpen, I establish and help manage author and editor acquisition and contact."}},relatedBooks:[{type:"book",id:"6957",title:"New Trends in Structural Engineering",subtitle:null,isOpenForSubmission:!1,hash:"8c26eaf65a25f29d43abd17ff651746f",slug:"new-trends-in-structural-engineering",bookSignature:"Hakan Yalciner and Ehsan Noroozinejad Farsangi",coverURL:"https://cdn.intechopen.com/books/images_new/6957.jpg",editedByType:"Edited by",editors:[{id:"72283",title:"Dr.",name:"Dr. Hakan",surname:"Yalciner",slug:"dr.-hakan-yalciner",fullName:"Dr. Hakan Yalciner"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1591",title:"Infrared Spectroscopy",subtitle:"Materials Science, Engineering and Technology",isOpenForSubmission:!1,hash:"99b4b7b71a8caeb693ed762b40b017f4",slug:"infrared-spectroscopy-materials-science-engineering-and-technology",bookSignature:"Theophile Theophanides",coverURL:"https://cdn.intechopen.com/books/images_new/1591.jpg",editedByType:"Edited by",editors:[{id:"37194",title:"Dr.",name:"Theophanides",surname:"Theophile",slug:"theophanides-theophile",fullName:"Theophanides Theophile"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3092",title:"Anopheles mosquitoes",subtitle:"New insights into malaria vectors",isOpenForSubmission:!1,hash:"c9e622485316d5e296288bf24d2b0d64",slug:"anopheles-mosquitoes-new-insights-into-malaria-vectors",bookSignature:"Sylvie Manguin",coverURL:"https://cdn.intechopen.com/books/images_new/3092.jpg",editedByType:"Edited by",editors:[{id:"50017",title:"Prof.",name:"Sylvie",surname:"Manguin",slug:"sylvie-manguin",fullName:"Sylvie Manguin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3161",title:"Frontiers in Guided Wave Optics and Optoelectronics",subtitle:null,isOpenForSubmission:!1,hash:"deb44e9c99f82bbce1083abea743146c",slug:"frontiers-in-guided-wave-optics-and-optoelectronics",bookSignature:"Bishnu Pal",coverURL:"https://cdn.intechopen.com/books/images_new/3161.jpg",editedByType:"Edited by",editors:[{id:"4782",title:"Prof.",name:"Bishnu",surname:"Pal",slug:"bishnu-pal",fullName:"Bishnu Pal"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"72",title:"Ionic Liquids",subtitle:"Theory, Properties, New Approaches",isOpenForSubmission:!1,hash:"d94ffa3cfa10505e3b1d676d46fcd3f5",slug:"ionic-liquids-theory-properties-new-approaches",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/72.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1373",title:"Ionic Liquids",subtitle:"Applications and Perspectives",isOpenForSubmission:!1,hash:"5e9ae5ae9167cde4b344e499a792c41c",slug:"ionic-liquids-applications-and-perspectives",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/1373.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"57",title:"Physics and Applications of Graphene",subtitle:"Experiments",isOpenForSubmission:!1,hash:"0e6622a71cf4f02f45bfdd5691e1189a",slug:"physics-and-applications-of-graphene-experiments",bookSignature:"Sergey Mikhailov",coverURL:"https://cdn.intechopen.com/books/images_new/57.jpg",editedByType:"Edited by",editors:[{id:"16042",title:"Dr.",name:"Sergey",surname:"Mikhailov",slug:"sergey-mikhailov",fullName:"Sergey Mikhailov"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"371",title:"Abiotic Stress in Plants",subtitle:"Mechanisms and Adaptations",isOpenForSubmission:!1,hash:"588466f487e307619849d72389178a74",slug:"abiotic-stress-in-plants-mechanisms-and-adaptations",bookSignature:"Arun Shanker and B. Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"878",title:"Phytochemicals",subtitle:"A Global Perspective of Their Role in Nutrition and Health",isOpenForSubmission:!1,hash:"ec77671f63975ef2d16192897deb6835",slug:"phytochemicals-a-global-perspective-of-their-role-in-nutrition-and-health",bookSignature:"Venketeshwer Rao",coverURL:"https://cdn.intechopen.com/books/images_new/878.jpg",editedByType:"Edited by",editors:[{id:"82663",title:"Dr.",name:"Venketeshwer",surname:"Rao",slug:"venketeshwer-rao",fullName:"Venketeshwer Rao"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"4816",title:"Face Recognition",subtitle:null,isOpenForSubmission:!1,hash:"146063b5359146b7718ea86bad47c8eb",slug:"face_recognition",bookSignature:"Kresimir Delac and Mislav Grgic",coverURL:"https://cdn.intechopen.com/books/images_new/4816.jpg",editedByType:"Edited by",editors:[{id:"528",title:"Dr.",name:"Kresimir",surname:"Delac",slug:"kresimir-delac",fullName:"Kresimir Delac"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"40538",title:"Management of Anemia on Hemodialysis",doi:"10.5772/52399",slug:"management-of-anemia-on-hemodialysis",body:'\n\t\tThe definition of anemia is controversial. The WHO defines anemia as hemoglobin (Hb)<13 g/dL for men and <12 g/dL for women [1]. The National Kidney Foundation\'s Kidney Disease Outcomes Quality Initiative, which is the criteria used for Medicare reimbursement, defines anemia in adult men and postmenopausal women as Hb<12 g/dL, or <11 g/dL in a premenopausal woman [2]. Anemia represents a significant problem to deal with in patients with chronic kidney disease (CKD) on hemodialysis (HD). Renal anemia is typically an isolated normochromic, normocytic anemia with no leukopenia or thrombocytopenia [3]. This is a frequent complication and contributes considerably to reduced quality of life (QoL) [4-6] of patients with CKD. It has also been associated with a number of adverse clinical outcomes, increased morbidity and mortality [5, 7-13]. In general, there is a progressive increase in the incidence and severity of anemia with declining renal function. The reported prevalence of anemia by CKD stage varies significantly and depends, to a large extent, on the definition of anemia and whether study participants selected from the general population, are at a high risk for CKD. Data from the National Health and Nutrition Examination Survey (NHANES) showed that the distribution of Hb levels starts to fall at an estimated glomerular filtration rate (eGFR) of less than 75 ml/min per 1.73 m2 in men and 45 ml/min per 1.73 m2 in women [14]. Among patients under regular care and known to have CKD, the prevalence of anemia was found to be much greater, with mean Hb levels of 12.8 ± 1.5 g/dl (CKD stages 1 and 2), 12.4 ± 1.6 g/dl (CKD stage 3), 12.0 ± 1.6 g/dl (CKD stage4), and 10.9 ± 1.6 g/dl (CKD stage 5) [15]. Although renal anemia is independent of the etiology of kidney disease, there are two important exceptions. Renal anemia in diabetic patients develops more frequently, at earlier stages of CKD, and more severely at a given level of renal impairment [16-18]. In patients with polycystic kidney disease, Hb is higher than in other patients with similar degrees of renal failure, and polycythemia may occasionally develop [19]. Many patients not yet on dialysis still receive no specific treatment for their anemia. In contrast, in patients on dialysis,, average Hb values have steadily increased during the past 15 years, following the advent of erythropoietin (EPO) and the development of clinical practice guidelines for anemia management [16, 17]. Anemia contributes to significant healthcare costs associated with CKD [20]. The average Hb value, however, varies considerably between countries, reflecting variability in practice patterns [21]. Before the availability of recombinant human erythropoietin (rhuEPO, or epoetin), patients on dialysis frequently required blood transfusions, exposing them to the risks of iron overload, transmission of viral hepatitis, and sensitization, which reduced the chances of successful transplantation. Anemia in CKD patients except from the lack of EPO [22, 23], is a multifactor process. Shorter lifespan of red blood cells, iron and vitamin deficiency due to dietary restrictions, and rarely bleeding that accompanies uremia seem to be other important factors [24, 25]. Adequate dialysis can contribute to anemia correction through many mechanisms, including the removal of molecules that may inhibit erythropoiesis using high-flux dialyzers [26-30]. It also seems that residual renal function is important in dialysis patients and its decline also contributes significantly to anemia, inflammation, and malnutrition in patients on dialysis [31, 32]. It is also affected by the underlying disease, co morbid conditions, malignancy, infection, heart failure, as mentioned above, the environment and several other factors (therapeutic treatment with angiotensin-converting enzyme(ACE) inhibitors, [33-37] increased PTH, [38-43] osteodystrophy [44, 45]) that differ among patients. Thus, anemia management in these patients needs an individualized approach. Each patient should be treated according to an Hb target with the lowest effective Erythropoiesis Stimulating Agents (ESA) dose, while avoiding large fluctuations in Hb levels or prolonged periods outside the target. This strategy may necessitate changes to the ESA dose, dosing frequency and iron supplementation over the course of a patient\'s treatment, and proactive management of conditions that can affect ESA responsiveness. While all ESAs effectively increase Hb levels, differences with respect to route of administration, pharmacokinetics, and dosing frequency and efficiency should be considered to maximize the benefits of ESA treatment for the individual patient [46]. Substitution of the subcutaneous route of administration for the intravenous route for epoetin-alfa can reduce drug acquisition and costs, the two largest components of healthcare costs in CKD patients [20]. Hence, treating anemia in CKD patients on HD seems to be very complex and has to be managed step by step correcting all the factors that affect this process.
\n\t\tThe diagnosis of anemia and the assessment of its severity are best made by measuring the Hb concentration rather than the hematocrit. Hb is a stable analyte measured directly in a standardized fashion, whereas the hematocrit is relatively unstable, indirectly derived by automatic analyzers, and lacking of standardization. Within-run and between-run coefficients of variation in automated analyzer measurements of Hb are one half and one third those for hematocrit, respectively [16]. There is considerable variability in the Hb threshold used to define anemia in CKD patients. According to the definition in the Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines, anemia should be diagnosed at Hb concentrations of less than 13.5 g/dl in adult men and less than 12.0 g/dl in adult women [16].These values represent the mean Hb concentration of the lowest 5th percentile of the sex-specific general adult population. In children, age-dependent differences in the normal values have to be taken into account. Normal Hb values are increased in high-altitude residents [16]. The end of the short interdialytic period is the most appropriate timing for anemia assessment [47]. Although renal anemia is typically normochromic and normocytic, [48, 49] deficiency of vitamin B12 or folic acid may lead to macrocytosis, whereas iron deficiency or inherited disorders of Hb formation (such as thalassemia) may produce microcytosis. Macrocytosis with leucopenia or thrombocytopenia suggests a generalized disorder of hematopoiesis caused by toxins, nutritional deficit, or myelodysplasia. Hypochromia probably reflects iron-deficient erythropoiesis. An absolute reticulocyte count, which normally ranges between 40,000 and 50,000 cells/μl of blood, is a useful marker of erythropoietic activity. Iron status tests should be performed to assess the level of iron in tissue stores or the adequacy of iron supply for erythropoiesis. Although serum ferritin is so far the only available marker of storage iron, several tests reflect the adequacy of iron for erythropoiesis, including transferrin saturation, MCV, and MCHC; the percentage of hypochromic red blood cells (PHRC); and the content of Hb in reticulocytes (CHr) [50]. Storage time of the blood sample may elevate PHRC, MCV and MCHC are below the normal range only after long-standing iron deficiency. It is important to identify anemia in CKD patients because it may signify nutritional deficits, systemic illness, or other conditions that warrant attention, and even at modest degrees, anemia reflects an independent risk factor for hospitalization, cardiovascular disease, and mortality [16, 51]. Drug therapy such as ACE inhibitors may reduce Hb levels by: firstly, direct effects of angiotensin II on erythroid progenitor cells, [52] secondly, accumulation of N-acetyl-seryl-lysyl-proline (Ac-SDKP), an endogenous inhibitor of erythropoiesis, [53] and thirdly, reduction of endogenous EPO production, potentially due to the hemodynamic effects of angiotensin II inhibition [54]. Myelosuppressive effects of immunosuppressants may further contribute to anemia [55].The measurement of serum EPO concentrations is usually not helpful in the diagnosis of renal anemia because there is relative rather than absolute deficiency, with a wide range of EPO concentrations for a given Hb concentration that extends far beyond the normal range of EPO levels on healthy, non-anemic individuals. Abnormalities of other laboratory parameters should be investigated, such as a low MCV or MCHC (may indicate an underlying hemoglobinopathy), a high MCV (may indicate vitamin B12 or folic acid deficiency), or an abnormal leukocyte or platelet count (may suggest a primary bone marrow problem, such as myeloma or myelodysplastic syndrome).
\n\t\tDue to the fact that anemia reduces tissue oxygenation, it is associated with widespread organ dysfunction and hence an extremely varied clinical picture. In mild anemia there may be no symptoms or simply increased fatigue and a slight pallor. As anemia becomes more marked the symptoms and signs gradually appear. Pallor is best discerned in the mucous membranes; the nailbeds and palmar creases, although often said to be useful sites for detecting anemia, are relatively insensitive for this purpose. Cardiorespiratory symptoms and signs include dyspnea, tachycardia, palpitations, angina or claudication, night cramps, increased arterial pulsation, capillary pulsation, a variety of cardiac bruits, reversible cardiac enlargement. Neuromuscular involvement is reflected by headache, vertigo, light-headedness, faintness, tinnitus, roaring in the ears, cramps, increased cold sensitivity. Acute anemia may occasionally give rise to papilledema. Gastrointestinal symptoms include loss of appetite, nausea, constipation, and diarrhea. Genitourinary involvement causes menstrual irregularities, urinary frequency, and loss of libido. There may also be a low-grade fever. In the elderly, to whom associated degenerative arterial disease is common, anemia may be manifested with the onset of cardiac failure. Alternatively, previously undiagnosed coronary narrowing may be unmasked by the onset of angina [56].
\n\t\t\tIn the early clinical trials of EPO performed in the late 1980s, the mean baseline Hb concentration was about 6 to 7 g/dl, and this progressively increased to about 11 or 12g/dl after treatment. Patients subjectively felt much better, with reduced fatigue, increased energy levels, and enhanced physical capacity, and there were also objective improvements in cardiorespiratory function [57]. Thus, it is now clear that many of the symptoms previously attributed to the “uremic syndrome” are indeed due to the anemia associated with CKD. Although the avoidance of blood transfusions and improvement in quality of life are obvious early changes, there are also possible effects on the cardiovascular system. The physiologic consequences of long-standing anemia are an increase in cardiac output and a reduction in peripheral vascular resistance. Anemia is a risk factor for the development of left ventricular hypertrophy in CKD patients and exacerbate left ventricular dilation. Sustained correction of anemia in CKD patients results in a reversal of most of these cardiovascular abnormalities, with the notable exception of left ventricular dilation. Once the left ventricle is stretched beyond the limits of its elasticity, correction of anemia cannot reverse this [58]. It may, however, prevent the development of LV dilation, and this leads to improved quality of life [59]. Anemia correction may improve QoL, [60, 61] cognitive function, sleep patterns, nutrition, sexual function, menstrual regularity, immune responsiveness, and platelet function [62-66].
\n\t\tAs mentioned above, renal anemia is a multifactor process and its treatment has to focus on a step by step correction of all factors which are involved in this process [67]. First of all, iron deficiency has to be treated before adding more expensive therapies such as EPO therapy.
\n\t\t\tIron is an essential ingredient for heme synthesis, and adequate amounts of this mineral are required for the manufacture of new red cells. Thus, under enhanced erythropoietic stimulation, greater amounts of iron are used, and many CKD patients have inadequate amounts of available iron to satisfy the increased demands of the bone marrow [68]. Patients with CKD, on HD treatments, may lose up to 3gr of iron each year because of frequent blood losses, so they are at particularly high risk of iron store depletion with subsequent iron deficiency anemia [17]. Even before the introduction of ESA therapy, many CKD patients were in negative iron balance as a result of poor dietary intake, poor appetite, and increased iron losses due to occult and overt blood losses. Losses on HD patients are up to 5 or 6 mg a day, compared with 1 mg on healthy individuals, and this may exceed the absorption capacity of the gastrointestinal tract, particularly when there is any underlying inflammation. Iron deficiency can be defined as absolute or functional [17, 68, 69]. Absolute iron deficiency develops as the body\'s iron stores become depleted to such a low level that not enough iron is available for the production of Hb [70, 71]. This is usually indicated by a decline in serum ferritin levels to ~<15 μg/l in patients with normal kidney function, [70, 71] or <12 ng/mL [72] according to other studies and TSAT levels below 16% [73]. Absolute iron deficiency in CKD patients has been defined as serum ferritin levels <100 ng/mL and TSAT levels <20%. The functional iron deficiency describes the state when iron cannot be mobilized from stores (despite an adequate dietary supply) to meet the demand for erythropoiesis [70]. Serum ferritin levels can appear normal (200–500 μg/l) or increased in chronic inflammatory disorders, [70] while levels of transferrin saturation (TSAT), which is serum iron divided by total iron-binding capacity, [68] will be low (typically <20%), indicating limited transport of iron to the erythron for erythropoiesis [70, 74, 75] and increased hypochromic red cells (>10%). The distinction between absolute and functional iron deficiency is crucial to understanding what constitutes adequate TSAT and serum ferritin levels on Epoetin-treated patients. The iron deficit limits the effectiveness of EPO therapy, and, to optimize the treatment, patients must receive an oral or intravenous (IV) iron supplement [76-78]. Thus, higher doses of ESAs may worsen iron depletion and lead to an increased platelet count (thrombocytosis), ESA hyporesponsiveness, and hemoglobin variability. Hence, ESA therapy requires concurrent iron supplementation [17, 79]. On the other hand, serum ferritin <200 ng/mL suggests iron deficiency in CKD patients, ferritin levels between 200 and 1,200 ng/mL may be related to inflammation, latent infections, malignancies, or liver disease. In part, this is due to the fact that, in addition to reflecting body iron stores, serum ferritin is also an acute phase reactant. As such, it can increase in the setting of either acute or chronic inflammation. Available data demonstrate that the lower the TSAT and the serum ferritin, the higher the likelihood that a patient is iron deficient, and the higher the TSAT and the serum ferritin, the lower the likelihood that a patient is iron deficient [77, 80]. A serum ferritin concentration of 100-500 ng/mL is the target during oral and intravenous (i.v.) iron therapy for pre-dialysis and peritoneal dialysis patients, but use of the i.v. route of administration and a target serum ferritin concentration of 200-500 ng/mL is recommended for HD patients by NKF [81]. Due to the fact that parenteral iron administration has potential risks that are immediate (eg, toxic effects and anaphylactic reactions) and long-term (e.g., decreased polymorphonuclear leukocyte function, increased risk of infections, organ damage), it is essential to select patients who need iron supplementation. Although oral iron administration is the primary treatment for iron deficiency, it has also disadvantages, such as poor iron absorption and adverse gastrointestinal reactions, which often lead to poor compliance. Oral iron is ineffective in many CKD patients, and parenteral iron administration is required, particularly on those receiving hemodialysis [68]. Nevertheless, even with these limitations of oral iron absorption, the cheap costs of using this route, along with convenience for the patient, often persuade physicians to try oral iron supplementation first on non-dialysis patients; if, however, there is insufficient response after 2 to 3 months, intravenous iron should be administered. However, the use of IV iron reduces the risk of adverse gastrointestinal reactions and overcomes the problem of poor compliance with oral therapy [82, 83]. Another advantage of the i.v. route is that the iron will not be eliminated by first-pass effects or by high efficiency dialysis membranes and the iron can be quickly released into the reticuloendothelial system and used for erythropoiesis, thus increasing its bioavailability. Intravenous iron administration may not only decrease hemoglobin variability and ESA hyporesponsiveness, it may also reduce the greater mortality associated with the much higher ESA doses that have been used in some patients when targeting higher hemoglobin levels [84]. Other, longer term concerns about intravenous administration of iron include the potential for increased susceptibility to infections and oxidative stress. Much of the scientific evidence for this has been generated in in vitro experiments, the clinical significance of which is unclear. There is emerging evidence that intravenous iron may improve the anemia of CKD in up to 30% of patients not receiving ESA therapy and have a low ferritin level [85]. Abnormalities of iron metabolism and anemia in chronic renal failure seem to correlate with levels of serum Hepcidin [86]. Hepcidin is a recently discovered protein of expeditious action produced in the liver and that may play an important role in iron homeostasis [87-89]. Hepcidin limits the absorption of iron from the intestine and iron release from macrophages and hepatocytes [90]. Iron absorption capacity in patients with CKD is considerably lower than in non-uremic individuals, particularly in the presence of systemic inflammatory activity, and this is probably mediated by Hepcidin up-regulation [91, 92]. The data in CKD and particularly in ESRD is limited both in hemodialysis and in peritoneal dialysis [93]. Because of its excretion in the urine [94, 95] and regulation by the presence or absence of inflammation, it is likely that its metabolism is affected by renal function and consistently influences the absorption of iron from the intestine and the stores of iron [96-99]. Originally due to the inability to measure serum levels of Hepcidin, its role in chronic kidney disease had not been adequately studied and most studies involved hepcidin’s levels in urine. It has been attempted to measure prohepcidin a precursor peptide of Hepcidin in CKD patients [100, 101]. According to our recently unpublished data Hepcidin levels were increased in hemodialysis patients in relation to normal individuals. The U.S. [16] and European [17] guidelines on renal anemia management suggest that the ferritin level be maintained in the range of 200 to500 μg/l, with an upper limit of 800 μg/l. Levels of ferritin above this threshold usually do not confer any clinical advantage and may exacerbate iron toxicity. The optimal transferring saturation is above 20% to 30% to ensure a readily available supply of iron to the bone marrow. Several studies support the maintenance of the percentage of hypochromic red cells at levels of less than 6%. Other measures of iron status, such as serum transferring receptor levels [102] and erythrocyte zinc protoporphyrin levels, are mainly research tools and have not been established in routine clinical practice. Intramuscular administration of iron is not recommended in CKD, given the enhanced bleeding tendency, the pain of the injection, and the potential for brownish discoloration of the skin. Thus, intravenous administration of iron has become the standard of care for many CKD patients, particularly those receiving hemodialysis [17, 68, 69, 103]. An important advantage of i.v. iron over oral iron is that it may bypass hepcidin actions by directly loading transferrin and making iron available to macrophages. Despite a reduction in the short-term risks, there is still concern about the potential for long-term toxicity of i.v. iron use (e. g. atherosclerosis development, infection and increased mortality) [104, 105] .The association of atherosclerosis with iron overload remains unclear. Alternatively, the relative risk for mortality or hospitalization from infection in patients undergoing HD and receiving i.v. iron was shown not to be higher than that observed in the overall HD population. Indeed, doses of i.v. iron up to 400 mg/month were associated with improved patient survival. There are several intravenous iron preparations available worldwide, including iron dextran, iron sucrose, and iron gluconate and Ferric carboxymaltose (table 1).
\n\t\t\t\t\n\t\t\t\t\t\t\tAVAILABLE IV IRON PREPARATIONS | \n\t\t\t\t\t\t\tMAXIMUM DOSE | \n\t\t\t\t\t\t\tADMINISTRATION | \n\t\t\t\t\t\t\tTEST DOSE | \n\t\t\t\t\t\t
Dextran Iron* | \n\t\t\t\t\t\t\t1000mg | \n\t\t\t\t\t\t\t0.0442 (Desired Hb - Observed Hb) x LBW + (0.26 x Lean body weight in kg) (For males: LBW = 50 kg + 2.3 kg for each inch of patient’s height over 5 feetFor females: LBW = 45.5 kg + 2.3 kg for each inch of patient’s height over 5 feet.) | \n\t\t\t\t\t\t\tA test dose of 25 mg diluted in 50 ml normal saline and infused over 5 minutes should be given. Infusion should then be stopped for 1 hour. If there is no reaction after 1 hour continue. | \n\t\t\t\t\t\t
Gluconate Iron* | \n\t\t\t\t\t\t\t125mg | \n\t\t\t\t\t\t\tThe recommended dosage of Sodium Ferric Gluconate for the repletion treatment of iron deficiency in hemodialysis patients is 10 mL of Ferrlecit (125 mg of elemental iron). Ferrlecit may be diluted in 100 mL of 0.9% sodium chloride administered by intravenous infusion over 1 hour per dialysis session | \n\t\t\t\t\t\t\tNo test | \n\t\t\t\t\t\t
Iron Sucrose* | \n\t\t\t\t\t\t\t500mg | \n\t\t\t\t\t\t\tAdminister Venofer 100 mg undiluted as a slow injection over 2 to 5 minutes, or as an infusion of 100 mg diluted in a maximum of 100 mL of 0.9% NaCl over a period of at least 15 minutes, per consecutive session. Venofer should be administered early during the dialysis session. | \n\t\t\t\t\t\t\tNo test dose | \n\t\t\t\t\t\t
Ferric Carboxymaltose** | \n\t\t\t\t\t\t\tA cumulative iron dose of 500 mg should not be exceeded for patients with body weight < 35 kg. A single dose of Ferinject should not exceed 1000 mg of iron (20 ml) per day. Do not administer 1000 mg of iron (20 ml) more than once a week. | \n\t\t\t\t\t\t\t1000 mg of iron during a minimum administration time of </=15 minutes. | \n\t\t\t\t\t\t\tNo test dose | \n\t\t\t\t\t\t
Avalaible i.v. iron preparations. *: www.globalrph.com - **: www.medicines.org.uk
All of these preparations contain elemental iron surrounded by a carbohydrate shell, which allows them to be injected intravenously. The liability of iron release from these preparations varies, with iron dextran being the most stable, followed by iron sucrose and then iron gluconate. Iron is released from these compounds to plasma transferrin and other iron-binding proteins and is eventually taken up by the reticulo-endothelial system. In hemodialysis patients, it is easy and practical to give low doses of intravenous iron (e.g., 10 to 20 mg every dialysis session) or, alternatively, 100 mg weekly. The more stable the iron preparation, the larger the dose administration rate that can be used. For example, 1gr of iron dextran may be given by intravenous infusion, whereas the maximum recommended dose of iron sucrose at any one time is 500 mg. For iron gluconate, doses in excess of 125 to 250 mg are best avoided. A 100 mg dose of iron sucrose is administered at 10 consecutive HD sessions. If after the end of the first 10-dose cycle patients remain iron deficient they complete another 10-dose cycle. If TSAT is 20-50% and SF 100-800 ng/mL, the patients start the maintenance regimen. If TSAT>50% or SF> 800 ng/mL then no further iron supplementation was deemed necessary. Iron replete patients received the iron maintenance regimen, consisting of 10 one weekly doses of up to 100 mg iron sucrose over 5 minutes. Iron repletion is defined as TSAT 20-50% and SF 100-800 ng/mL [106, 107]. Iron sucrose appears to offer the most favorable safety profile when compared to iron dextran and sodium ferric gluconate in treating hemodialysis patients. Oxidative stress and hypersensitivity reactions are common problems encountered when administering intravenous iron [108]. Therapy with dextran-free iron formulations is an essential part of anemia treatment protocols, and was not found to be associated with either short- or long-term serious side-effects [109]. Results suggest that 200 mg/FeIV/month is effective and that, of the markers tested, TSAT would be the most suitable one to the practicing nephrologist so as to optimize intravenous iron in the long run [110]. Sodium ferric gluconate is well tolerated when given by intravenous push without a test dose [111]. SFGC has a significantly lower incidence of drug intolerance and life-threatening events as compared to previous studies using iron dextran. The routine use of iron dextran in hemodialysis patients should be discontinued [112]. Nevertheless, older i.v. iron formulations have their limitations, including the potential for immunogenic reactions induced by dextran molecules (iron dextran) [113], dose limitations, a slow rate of administration (to prevent acute, labile iron-induced toxicity and vasoactive reactions) [70, 113] and the compulsory requirement for a test dose (iron dextrans in USA [114] and Europe. All-event reporting rates were 29.2, 10.5 and 4.2 reports per million 100 mg iron dose equivalents, while all-fatal-event reporting rates were 1.4, 0.6 and 0.0 reports per million 100 mg dose equivalents for iron dextran, sodium ferric gluconate and iron sucrose, respectively [115]. Recently, two new iron preparations have become available for intravenous use (ferumoxytol in the United States and ferric carboxymaltose in Europe) [116]. Both of these compounds allow higher doses of intravenous iron to be administered rapidly as a bolus injection, without the need for a test dose. Ferric carboxymaltose [FCM; FerinjectR; Vifor (International) Inc., St Gallen, Switzerland] is a next-generation parenteral, dextran-free iron formulation designed to overcome the limitations of existing i.v. iron preparations. The FCM is a macromolecular ferric hydroxide carbohydrate complex, composed of a poly-nuclear iron(III) hydroxide complexed to carboxymaltose [117]. As FCM is a strong and robust iron complex, and it can be administered in high doses, it does not release large amounts of reactive (‘free’) iron into the circulation and does not trigger dextran- associated immunogenic reactions [111, 117-119]. All intravenous iron preparations carry a risk for immediate reactions, which may be characterized by hypotension, dizziness, and nausea. These reactions are usually short-lived and caused by too large a dose given during too short a time. Iron dextran also carries the risk for acute anaphylactic reactions due to preformed dextran antibodies, and although this risk may be less with the lower molecular weight iron dextrans, the potential for anaphylaxis still remains. In such patients, a response to intravenous iron alone may occur within 2 to 3 weeks of iron administration. In those already receiving ESAs, there is considerable evidence that concomitant intravenous iron may enhance the response to the ESAs and result in lower dose requirements [17, 21, 68]. Ferric carboxymaltose also replenishes depleted iron stores and improves health-related quality-of-life (HR-QoL) on patients with iron-deficiency anemia. FCM is at least as effective as iron sucrose and as ferrus sulfate with regards to end point relative to serum ferritin, transferrin saturation and HR-QoL. Commonly reported drug-related adverse events include headache, dizziness, nausea, abdominal pain, constipation, diarrhea, rash and injection-site reactions. The incidence of drug-related adverse events on patients receiving intravenous FCM was generally similar to that in patients receiving oral ferrous sulfate. In general, rash and local injection-site reactions were more common with ferric carboxymaltose, whereas gastrointestinal adverse events were more frequent with ferrous sulfate [120]. Based on the No-Observed-Adverse-Effect-Levels (NOAELs) found in repeated-dose toxicity studies and on the cumulative doses administered, FCM has good safety margins. Lastly, no evidence of irritation was found in local tolerance studies with FCM [70]. Ferric carboxymaltose may represent a cost-saving option compared with the most likely alternative existing therapies used for the management of anemia [121, 122].
\n\t\t\tVitamin abnormalities in patients with CKD are frequent and appear early even with mild renal failure; fat-soluble vitamin supplements (A and E) should be avoided and their dietary intake limited [123]. Deficiency and/or altered metabolism of vitamins in ESRD is caused by uremic toxins, dietary restrictions, catabolic illness, losses during dialysis and drug interaction. In patients with polyneuropathy high doses of thiamine pyrophosphate (Cocarboxylase), given i.v., can be helpful in this respect. There are conflicting reports concerning plasma level of vitamin B2 (riboflavin) in ESRD patients. Some authors recommend its supplementation. The majority of patients with ESRD exhibit biochemical and clinical signs of vitamin B6 deficiency. A univocal opinion exists that supplementation of this vitamin effects the cellular immune system and the amino acid metabolism as well. An adequate dose of vitamin B6 is still a matter of dispute. Evidence of vitamin B12 deficiency has been reported rarely, thus, only few authors recommend the supplementation of it, mainly in CAPD patients. According to most authors the losses of folic acid and ascorbic acid during dialysis require oral supplementation. Despite the divergences in opinions concerning the deficiency of water-soluble vitamins in ESRD patients, the supplementation of these vitamins is practiced in many nephrological centers. The amount and the route of vitamins, administered to ESRD patients, should be individualized [124-126]. In ESRD patients under maintenance hemodialysis, oral L-carnitine supplementation may reduce triglyceride and cholesterol and increase HDL and hemoglobin and subsequently reduce needed erythropoietin dose without effect on QoL [127]. Adjuvant therapy includes: iron, vitamin C and D, L-carnitine, folic acid, cytokines and growth factors. Vitamin C (500 mg, after every hemodialysis) is very helpful in cases of functional iron deficiency. L-carnitine stabilizes the membrane of erythrocytes and prolongs their lives. Folic acid (10 mg/day) enhances response to EPO [128]. According to other authors supplementations of pyridoxine in the dose of 20 mg/day and of folic acid 5 mg/week in hemodialyzed patients during erythropoietin treatment are necessary [129].
\n\t\t\tErythropoiesis is a complex physiologic process through which homeostasis of oxygen levels in the body is maintained. It is primarily regulated by EPO, a 30-kD, 165–amino acid hematopoietic growth factor that is produced primarily by renal tubular and interstitial cells. Under normal conditions, endogenous EPO levels change according to O2 tension. EPO gene expression is induced by hypoxia-inducible transcription factors (HIF) [130]. In the presence of EPO, bone marrow erythroid precursor cells proliferate and differentiate into red blood cells. In its absence, these cells undergo apoptosis [131]. Endogenous EPO and rHuEPO share the same amino acid sequence, with slight but functionally important differences in the sugar profile. In clinical practice, rHuEPO is typically administered as a bolus injection, and the dosage is titrated to give the desired effect [131]. There is no significant difference between once weekly versus thrice weekly subcutaneous administration of rHu EPO. Once weekly administration of rHu EPO would require an additional 12U/kg/week for patients on hemodialysis [132].
\n\t\t\t\tRecombinant human erythropoietin has been used for more than 20 years for the treatment of renal anemia, revolutionizing its treatment in patients with CKD when it was approved for use in the United States in 1989, [133, 134] with epoetin-alfa and -beta representing the common traditional preparations. By the modification of the molecule\'s carbohydrate moiety or structure a longer duration of erythropoietin receptor stimulation was achieved. The administration of darbepoetin or C.E.R.A. once or twice a month is also sufficient to achieve serum hemoglobin target levels, [135] making the treatment safer and more comfortable both for the patients and the personnel. These synthetic erythropoietin receptor stimulating molecules, along with recombinant human erythropoietin, are together called "Erythropoiesis Stimulating Agents". The recombinant human erythropoietins and allied proteins (epoetin-alfa, attempted copies and biosimilar variants of epoetin-alfa, epoetin beta, epoetin delta, epoetin zeta, epoetin theta, epoetin omega, darbepoetin-alfa, and methoxy-polyethylene glycol-epoetin beta) are among the most successful and earliest examples of biotechnologically manufactured products to be used in clinical medicine (Table 2) [136].
\n\t\t\t\t\n\t\t\t\t\t\t\tAVALAIBLE ESAs | \n\t\t\t\t\t\t\tDOSE REGIMEN | \n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\tPrototype\n\t\t\t\t\t\t\t | \n\t\t\t\t\t\t\t\n\t\t\t\t\t\t |
epoetin-alfa* | \n\t\t\t\t\t\t\tCorrection phase: 50 IU/kg, 3 times per week. When a dose adjustment is necessary, this should be done in steps of at least four weeks. At each step, the increase or reduction in dose should be of 25 IU/kg, 3 times per week. Maintenance phase: Dosage adjustment in order to maintain haemoglobin values at the desired level: Hb between 10 and 12 g/dl (6.2 - 7.5 mmol/l). The recommended total weekly dose is between 75 and 300 IU/kg. \n\t\t\t\t\t\t\t | \n\t\t\t\t\t\t
epoetin beta* | \n\t\t\t\t\t\t\t1. Correction phase - Subcutaneous administration: - The initial dosage is 3 x 20 IU/kg body weight per week. The dosage may be increased every 4 weeks by 3 x 20 IU/kg and week if the increase of Hb is not adequate (< 0.25 g/dl per week). - The weekly dose can also be divided into daily doses. - Intravenous administration: The initial dosage is 3 x 40 IU/kg per week. The dosage may be raised after 4 weeks to 80 IU/kg three times per week - and by further increments of 20 IU/kg if needed, three times per week, at monthly intervals. For both routes of administration, the maximum dose should not exceed 720 IU/kg per week. 2. Maintenance phase To maintain an Hb of between 10 and 12 g/dl, the dosage is initially reduced to half of the previously administered amount. Subsequently, the dose is adjusted at intervals of one or two weeks individually for the patient (maintenance dose). \n\t\t\t\t\t\t\t | \n\t\t\t\t\t\t
darbepoetin-alfa* | \n\t\t\t\t\t\t\tCorrection phase: The initial dose by subcutaneous or intravenous administration is 0.45 µg/kg body weight, as a single injection once weekly. If the rise in haemoglobin is greater than 2 g/dl (1.25 mmol/l) in four weeks reduce the dose by approximately 25%.Dosing should be titrated as necessary to maintain the haemoglobin target. If a dose adjustment is required to maintain haemoglobin at the desired level, it is recommended that the dose is adjusted by approximately 25% \n\t\t\t\t\t\t\t | \n\t\t\t\t\t\t
Methoxy-polyethylene glycol-epoetin beta* | \n\t\t\t\t\t\t\ta starting dose of 0.6 microgram/kg bodyweight may be administered once every two weeks as a single intravenous or subcutaneous injection in patients on dialysis or not on dialysis. The dose may be increased by approximately 25% of the previous dose if the rate of rise in haemoglobin is less than 1.0 g/dl (0.621 mmol/l) over a month. Further increases of approximately 25% may be made at monthly intervals until the individual target haemoglobin level is obtained. | \n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\tBiosimilar\n\t\t\t\t\t\t\t | \n\t\t\t\t\t\t\t\n\t\t\t\t\t\t |
epoetin zeta* | \n\t\t\t\t\t\t\t1. Correction phase: 50 IU/kg 3 times per week. When a dose adjustment is necessary, this should be done in steps of at least four weeks. At each step, the increase or reduction in dose should be of 25 IU/kg 3 times per week. 2. Maintenance phase: Dose adjustment in order to maintain haemoglobin (Hb) values at the desired level: Hb between 10 and 12 g/dl (6.2-7.5 mmol/l). The recommended total weekly dose is between 75 and 300 IU/kg. \n\t\t\t\t\t\t\t | \n\t\t\t\t\t\t
epoetin delta** | \n\t\t\t\t\t\t\tFor Epoetin delta it is recommended to adjust the dose individually to maintain the target haemoglobin in the range 10 to 12 g/dl. A starting dose is recommended of 50 IU/kg three times a week if given intravenously or twice a week if given subcutaneously | \n\t\t\t\t\t\t
epoetin omega*** | \n\t\t\t\t\t\t\tStarting with 20 to 50 IU / kg three times a week, with a gradual increase in dose or frequency of issuance before the impact. Beyond hemoglobin levels to 12 g / m and Hematocrit-35 %. Dose reduction or no treatment. If there Effect dose increase to 40 to 55 IU / kg three times a week for two weeks, if necessary, until 60-75 IU / kg The course continues until the level Hematocrit (35 vol. %) And hemoglobin (12 g / m); Total weekly dose should not exceed 225 IU / kg supporting-60 IU / kg per week for 2-3 reception | \n\t\t\t\t\t\t
epoetin theta** | \n\t\t\t\t\t\t\tCorrection phase Subcutaneous administration: The initial posology is 20 IU/kg body weight 3 times per week. The dose may be increased after 4 weeks to 40 IU/kg, 3 times per week, if the increase in haemoglobin is not adequate (< 1 g/dl [0.62 mmol/l] within 4 weeks). Further increases of 25% of the previous dose may be made at monthly intervals until the individual target haemoglobin level is obtained. Intravenous administration: The initial posology is 40 IU/kg body weight 3 times per week. The dose may be increased after 4 weeks to 80 IU/kg, 3 times per week, and by further increases of 25% of the previous dose at monthly intervals, if needed. For both routes of administration, the maximum dose should not exceed 700 IU/kg body weight per week. Maintenance phase The dose should be adjusted as necessary to maintain the individual target haemoglobin level between 10 g/dl (6.21 mmol/l) to 12 g/dl (7.45 mmol/l), whereby a haemoglobin level of 12 g/dl (7.45 mmol/l) should not be exceeded. If a dose adjustment is required to maintain the desired haemoglobin level, it is recommended that the dose be adjusted by approximately 25%. Subcutaneous administration: The weekly dose can be given as one injection per week or three times per week. Intravenous administration: Patients who are stable on a three times weekly dosing regimen may be switched to twice-weekly administration. If the frequency of administration is changed, haemoglobin level should be monitored closely and dose adjustments may be necessary. The maximum dose should not exceed 700 IU/kg body weight per week | \n\t\t\t\t\t\t
Available ESAs worldwide. *: ww.medicines.org.uk, **: www.ema.europa.eu, ***: www.pharmabook.net
In hemodialysed patients the intravenous route is preferred, but the subcutaneous administration can substantially reduce dose requirements [137-139]. However, there are studies according to which conversion from SC to IV epoetin administration did not result in changes in Hb levels or epoetin dosage requirements in iron-replete hemodialysis patients, [140] but it seems that SC route of administration was associated with modestly higher hemoglobin variability [138].
\n\t\t\t\tThere are ongoing clinical trials with erythropoiesis stimulating molecules that can be administered by inhalation or per os [137]. It is also known from other studies that some co-morbidities like antecedents of malignant neoplasm are associated with EPO responsiveness [141]. In a pre-dialysis population, female gender, cardiovascular disease, malnutrition and inflammation are associated with ESA hyporesponsiveness [142]. EPO resistance in a pediatric dialysis cohort was predicted by nutritional deficits, inflammation, poor dialysis, and hyperparathyroidism, while iron and folic acid deficits were the major determinants in adults. Although confounded by the pattern of EPO prescription, neither age nor gender was predictive of EPO resistance in the two study groups [143]. Additionally delivered dialysis (Kt/ V(urea)) does not seem to be a significant predictor of erythropoietin responsiveness [144]. It also seems that there is difference in EPO hyporesponsiveness prevalence among different countries and different modalities [145]. The proportion of age has a limited influence on the level of anemia in pre-dialysis patients and is similar in both genders [146] There are, although, studies according to which there is higher proportion of anemia in female patients [147]. In a multicenter study with 8154 dialysis patients, females, blacks, patients between 18 and44 years old on hemodialysis less than six months exhibited significantly lower mean hemoglobin values despite being prescribed, on average, significantly higher epoetin alfa doses than males, whites and older patients, on hemodialysis more than six months. A significant regional variation in the prescribing patterns for s.c. epoetin alfa and i.v. iron has been described in this study [148]. Comparisons between patients from western and from eastern/central Europe show that patients from eastern/central Europe are less likely to receive epoetin treatment before starting dialysis, and have lower Hb concentrations at the start of epoetin treatment as well as at the start of dialysis [149]. In another multicenter study by Nissenson et al. there were wide variations in hemoglobin response rate among patients on hemodialysis, hemofiltration and hemodiafiltration [150].
\n\t\t\t\tOther factors such as cytokines like IL6 are induced by malignant tumors and may impair erythropoiesis. Also, TNF-α is known to inhibit this pathway [151]. Low ESA responsiveness was associated with higher mortality in both HD and PD patients [152]. In patients with persistently low Hb levels, mortality risk is strongly associated with the patient\'s ability to achieve a hematopoietic response rather than the magnitude of EPO dose titrations [153]. ESA dosing may be directly associated with risk of death, but the nature of the association likely varies according to hemoglobin concentration. Small doses with hemoglobin ≤12 g/dl and large doses with hemoglobin ≥10 g/dl may both be associated with poor outcomes [154].
\n\t\t\t\tSerum albumin concentration is an important predictor of both baseline Hb and EPO sensitivity in chronic hemodialysis patients. Factors that improve serum albumin may also improve Hb in hemodialysis patients [155]. Hyperleptinemia reflects better nutritional status and rHuEPO response in long-term HD patients. Increasing energy intake improves erythropoiesis, which may be mediated in part by an increase in serum leptin levels [156, 157]. Statin therapy may improve responsiveness to erythropoietin-stimulating agents in patients with end-stage renal disease, increasing erythropoiesis by targeting hepcidin and iron regulatory pathways, independent of erythropoietin [158, 159]. The initial and sustained erythropoietic responses are independent from each other and are associated with different factors. Treatment focusing on these factors may improve the response [160]. A pleiotropic effect of EPO has been shown in the kidney, the central nervous system, and the cardiovascular system, [161] such as significant slowing of progression and substantial retardation of maintenance dialysis [162, 163].
\n\t\t\t\tAlthough ESA use in patients with chronic kidney disease or/and on dialysis were studied extensively, the optimal target hemoglobin concentration as well as the required ESA dose and dosing interval to achieve this concentrations remain elusive (NHS, CREATE, CHOIR and TREAT) [164-167]. Hb can be increased with erythropoiesis-stimulating proteins (ESPs); however, 5-10% of patients respond poorly. The patient incidence of hyporesponse seems to be around 14%, and a mean 9% of patients is hyporesponsive at any given time. The most common potential causes of hyporesponse is iron deficiency (being reported in 39% of hyporesponse events), medication (immunosuppressive agents, ACE inhibitors), secondary hyperparathyroidism [168] and inflammation/malnutrition [169]. The safety profile of epoetin-alfa and darbepoetin-alfa are similar, but the longer half-life of darbepoetin-alfa permits administration on a once a week or once-monthly basis in patients with CKD and anemia. Extended dosing of CERA also appears safe and effective on dialysis patients with CKD [81].
\n\t\t\t\t\n\t\t\t\t\tEpoetin alfa: is a recombinant form of erythropoietin, a glycoprotein hormone which stimulates red blood cell production by stimulating the activity of erythroid progenitor cells. Intravenous and subcutaneous therapy with epoetin alfa raises hematocrit and hemoglobin levels, and reduces transfusion requirements, in anemic patients with end-stage renal failure undergoing hemodialysis. The drug is also effective in the correction of anemia on patients with chronic renal failure not yet requiring dialysis and does not appear to affect renal hemodynamics adversely or to precipitate the onset of end-stage renal failure. Epoetin alfa does not appear to exert any direct cerebrovascular adverse effects [170]. Administration of epoetin alfa at once weekly and fortnightly intervals are potential alternatives to three times per week dosing for the treatment of anemia [171-173].
\n\t\t\t\t\n\t\t\t\t\tEpoetin beta: is a recombinant form of erythropoietin. The drug binds to and activates receptors on erythroid progenitor cells which then develop into mature erythrocytes. Epoetin beta increases reticulocyte counts, hemoglobin levels and hematocrit in a dose-proportional manner. Increases of 15 to 54% in hemoglobin levels and 17 to 60% in hematocrit were reported after subcutaneous or intravenous epoetin beta therapy in studies of 8 weeks\' to 12 months\' duration. Comparative data indicate that dosage reductions of approximately 30% compared with intravenous therapy are possible when subcutaneous administration of epoetin beta is used. Hematocrit increased more rapidly in 5 multicenter studies on patients who received epoetin beta subcutaneously than on those who received the same dosage intravenously. It also causes significant improvements on quality of life, exercise capacity and overall well-being. Results of clinical studies indicate that subcutaneous administration is desirable where possible in the majority of patients [174].
\n\t\t\t\t\n\t\t\t\t\tDarboepoetin-alfa: It is a hyperglycosylated analog of recombinant human erythropoietin with the same mechanism of action as erythropoietin, but with a three-fold longer terminal half-life after intravenous administration than recombinant human erythropoietin and the native hormone both in animal models and in humans. It is administered less frequently (once weekly or every other week) [175, 176]. The recommended starting dose in chronic renal failure patients is 0.45mcg/kg once weekly for both intravenous and subcutaneous administration, with subsequent titration based on the hemoglobin concentration. The adverse event profile of darbepoetin-alfa is similar to that of recombinant human erythropoietin in both settings, [177, 178] and effectively maintains hemoglobin in the target range in dialysis patients with renal anemia [179]. It also has been shown to be effective when administered once/week and once every 2, 3, or 4 weeks [180]. There are no reports of antibody formation associated with darbepoetin-alfa on chronic renal failure patients, and three cases of antibody formation, with neutralizing activity in one of the cases, reported on cancer patients [181-184].
\n\t\t\t\t\n\t\t\t\t\tCera: Methoxy polyethylene glycol-epoetin beta (MPG-EPO; Mircera®, Roche, Basel, witzerland) is an agent that has a different interaction with the erythropoietin receptor than previous agents and has a long elimination half-life (approximately 130 hours) [185]. MPG-EPO is the only ESA generated by chemical modification of glycosylated erythropoietin, by the integration of one specific, long, linear chain of polyethylene glycol. The resultant molecule has a molecular weight of approximately 60 kDa, which is twice that of epoetin. The methoxy polyethylene glycol polymer chain is integrated through amide bonds between the N-terminal amino group or the ε-amino group (predominantly lysine-52 or lysine-45) with a single butanoic acid linker [186]. In ESA-naïve patients, the recommended starting dose is 0.6 µg/kg administered once every 2 weeks as a subcutaneous or intravenous injection, in order to reach a hemoglobin level of.11 g/dL. The dose may be increased by approximately 25% if hemoglobin levels increase by, 1.0 g/dL over a month. Further increases of approximately 25% may be made once per month until the individual target hemoglobin level is reached. If a hemoglobin level of.11 g/dL is reached for an individual patient, MPG-EPO may be continued once per month using a dose equal to twice the previous dose once every 2 weeks. Patients currently being treated with ESA can be directly converted to MPG-EPO administered once per month as a single intravenous or subcutaneous injection. The starting dose of this agent is based on the calculated weekly equivalent dose of DA or epoetin at the time of conversion [187]. The first injection of MPG-EPO should start at the next scheduled dose of the previously administered DA or epoetin dose. On patients receiving treatment with ESA and those naïve to ESA, the MPG-EPO dose should be reduced by approximately 25% if the hemoglobin level increases by more than 2 g/dL in 1 month or if the hemoglobin level approaches 12 g/dL. If hemoglobin levels continue to increase, MPG-EPO administration should be interrupted until these levels begin to decrease (a decrease of approximately 0.35 g/dL per week is expected). Therapy should then be resumed at a dose approximately 25% less than the previously administered dose. Dose adjustments should not be made more frequently than once per month [17, 188]. Once-monthly CERA therapy maintains stable Hb values with low intra-individual variability and few dose adaptations in hemodialysis patients when administered entirely according to local practice, and the regimen is well-tolerated [189]. C.E.R.A. can be administered to patients at any time during hemodialysis or hemofiltration without appreciable loss in the extracorporeal circuit [190].
\n\t\t\t\t\n\t\t\t\t\tPeginesatide (formerly known as Hematide™): is a synthetic, peptide-based erythropoiesis-stimulating agent linked to polyethylene glycol. Based on extensive preclinical and clinical data substantiating the efficacy and safety of this agent, it was approved in the U.S. in March 2012 for the treatment of anemia due to chronic kidney disease in adult patients on dialysis. Peginesatide (Omontys®) was launched in the U.S. in April 2012 [191, 192]. A drug capable of stimulating erythropoiesis is the first ESA that bears no structural similarity to rhuEPO. Peginesatide is a synthetic, dimeric peptide that is covalently linked to polyethylene glycol (PEG). Peginesatide binds to and activates the human EPO receptor, stimulating the proliferation and differentiation of human red cell precursors in vitro in a manner similar to ESAs [193]. Peginesatide administered once monthly was as effective as epoetin alfa given thrice weekly (dialysis patients) or darbepoetin given once weekly (nondialysis patients), in correcting anemia of chronic kidney disease as well as maintaining hemoglobin within the desired target range [194-196].
\n\t\t\t\n\t\t\t\t\tEpoetin zeta: Epoetin zeta is therapeutically equivalent to epoetin alfa in the maintenance of target Hb levels on patients with renal anemia. No unexpected adverse effects were seen [197-201].
\n\t\t\t\t\n\t\t\t\t\tEpoetin theta: Has efficacy comparable with epoetin beta (s.c.) in pre-dialysis patients with renal anemia based on Hb changes from baseline to end of treatment (non-inferiority). The safety profile was also comparable. Patients could be switched from maintenance treatment with epoetin beta to epoetin theta without relevant dose changes [202].
\n\t\t\t\t\n\t\t\t\t\tEpoetin omega: Epoetin-omega is a sialoglycoprotein with smaller amounts of O-bound sugars, less acidic and with different hydrophylity than the other 2 epoetins. The initial weekly dose of epoetin-omega was 90 units per kg of body weight (b.w.) divided in 3 equal portions and administered subcutaneously after each dialysis session. After correction of the hemoglobin, the dose of rHuEPO was individualized to keep Hb within target limits of 100-120 g/l. The mean dose of epoetin-omega during the correction period never exceeded 100 U/kg b.w. per week and the average maintenance dose between 50-60 U/kg b.w. per week [203, 204].
\n\t\t\t\t\n\t\t\t\t\tHX575: Is a biosimilar version of epoetin-α that is approved for the treatment of anemia associated with chronic kidney disease (CKD) using the intravenous route of administration [205, 206]. In a study for S.C. use two patients developed neutralizing antibodies (NAbs) to erythropoietin, which resulted in the study being terminated prematurely [207].
\n\t\t\tAdverse effects of EPO therapy are uncommon, apart from a moderate increase in blood pressure and an increased rate of vascular access thrombosis. In spite of the fact that, these effects are probably dependent to a large degree on the increase in Hb concentrations, there are some concerns that ESA therapy may enhance thrombogenicity and tumor growth on patients with malignant disease as well as exacerbate vascular events in CKD independently of Hb concentrations [208]. In treatment with epoetin alfa hypertension occurs in 30 to 35% of patients with end-stage renal failure, but this can be managed successfully with correction of fluid status and antihypertensive medication where necessary, and is minimized by avoiding rapid increases in hematocrit. Although vascular access thrombosis has not been conclusively linked to therapy with the drug, increased heparinisation may be required when it is administered to patients on hemodialysis [170]. On patients who receive epoetin beta, hypertension may occur but may be minimized by avoiding rapid increases in hematocrit (> 0.5%/week), and is managed in most cases with control of fluid status and antihypertensive medication. Although clotting of the vascular access has not been conclusively linked to epoetin beta, caution is recommended on patients undergoing hemodialysis. Increased heparinisation is recommended to prevent clotting in dialysis equipment [174]. Before 1998, EPO alfa in Europe was formulated with human serum albumin, but because of a change in European regulations, this was replaced with polysorbate 80. EPO beta is formulated with polysorbate 20, along with urea, calcium chloride, and five amino acids as excipients. The importance of the formulation of the EPO products was highlighted in 2002 with an upsurge in cases of antibody-mediated pure red cell aplasia in association with the subcutaneous use of EPO alfa after its change for indicate mulation. Patients affected by this complication develop neutralizing antibodies against both rhuEPO and the endogenous hormone, which result in severe anemia and transfusion dependence [209, 210]. The cause of this serious complication in which there is a break in B-cell tolerance remains obscure, although it seems likely that factors such as a breach of the cold storage chain were relevant, and the subcutaneous application route was a prerequisite; circumstantial evidence also suggested that rubber stoppers of prefilled syringes used in one of the albumin-free EPO alfa formulations may have released organic compounds that acted as immunologic adjuvants [211].
\n\t\t\tThere has been considerable debate in recent times about the optimal target range of Hb in CKD patients [133]. The improvement in quality of life with increasing Hb concentrations supports a level above 10 to 11 g/dl in all CKD patients, [16, 17] but some studies have indicated increased risks associated with attempts to completely correct anemia. No survival benefit is evident at a higher level of anemia correction, [13, 164, 165, 167] although quality of life and exercise capacity may be greater. Thus, there is a possible tradeoff between improved quality of life and increased cost and risk for harm, so that a target level of Hb above 13 g/dl should be avoided [16]. Clinical trials of erythropoiesis-stimulating agents indicate that targeting the complete correction of anemia in patients with chronic kidney disease results in a greater risk of morbidity and mortality despite improved hemoglobin and quality of life [59, 164, 212]. Although there are studies that state the opposite [213, 214]. Relationships between hemoglobin concentration and mortality differed between African Americans and whites. Additionally, the relationship of lower mortality with greater achieved hemoglobin concentration seen in white patients was observed for all-cause, but not cardiovascular mortality [215]. Erythropoiesis-stimulating agents should be used to target hemoglobin 11-12 g/dl on patients with chronic kidney disease. However, a risk-benefit evaluation is warranted in individual patients, and high ESA doses driven by hyporesponsiveness should be avoided [216]. Intravenous iron may be beneficial for patients with hemoglobin less than 11 g/dl and transferrin saturation less than 25% despite elevated ferritin (500-1200 ng/ml) [217, 218]. TREAT and other large randomized, controlled trials of ESA treatment on patients with CKD have not demonstrated a clinical benefit in terms of mortality, morbidity, or quality of life improvement of targeting Hb levels greater than 12-13 g/dl. Some of these studies have demonstrated increased risk of stroke, vascular access thrombosis, hypertension, and other events [219]. The European Renal Best Practice (ERBP), which are issued by ERA-EDTA, are suggestions for clinical practice in areas in which evidence is lacking or weak, together with position statements on published randomized controlled trials, or on existing guidelines and recommendations. In 2009, the Anemia Working Group of ERBP published its first position statement about the hemoglobin target to aim for with erythropoietin-stimulating agents (ESA) and on issues that were not covered by K-DOQI in 2006-07. Following the findings of the TREAT study, the Anemia Working Group of ERBP maintains its view that \'Hb values of 11-12 g/dL should be generally sought in the CKD population without intentionally exceeding 13 g/dL and that the doses of ESA therapy to achieve the target hemoglobin should also be considered. More caution is suggested when treating anemia with ESA therapy on patients with type 2 diabetes not undergoing dialysis (and probably in diabetics at all CKD stages). To those with ischemic heart disease or with a previous history of stroke, possible benefits should be weighed up against an increased risk of stroke recurrence, when deciding which Hb level to aim for. These recommendations are not intended to represent a new guideline as they are not the result of a systematic review of evidence [220]. The National Kidney Foundation (NKF) and the Food and Drug Administration (FDA) recommend different target levels for hemoglobin in patients with terminal kidney disease treated by hemodialysis [79, 221]. The NKF recognizes also the importance of individualizing the treatment of anemia. The optimal range of target hemoglobin levels in Kainz et al analysis of hemodialysis patients was 11 g/day. Furthermore, ESA hypo-responders showed an increased risk of mortality with higher hemoglobin levels, and ESA responders actually exhibited a decreased risk [222]. A corrected weekly ESA dose up to 16 000 units with achieved hemoglobin levels ~11 g/dL exhibited the lowest mortality risk. Hemoglobin variability as well as ESA hypo-response causing low hemoglobin levels was associated with a numerically increased risk of mortality compared with patients with stable hemoglobin levels between 10 and 12 g/dL. Furthermore, ESA response requiring more than 16 000 units per week was also associated with an increased risk of death in ESA responders [222]. The Japanese Society for Dialysis Therapy (JSDT) guideline committee presents the Japanese guidelines entitled "Guidelines for Renal Anemia in Chronic Kidney Disease." These guidelines replace the "2004 JSDT Guidelines for Renal Anemia in Chronic Hemodialysis Patients," and contain new, additional guidelines for peritoneal dialysis (PD), non-dialysis (ND), and pediatric CKD patients [223]. Values for diagnosing anemia are based on the most recent epidemiological data from the general Japanese population. To both men and women, Hb levels decrease along with an increase in age and the level for diagnosing anemia has been set at <13.5 g/dL on males and <11.5 g/dL on females. Renal anemia is identified as an "endocrine disease." It is believed that in this way defining renal anemia will be extremely beneficial for ND patients exhibiting renal anemia despite having a high GFR. We have also emphasized that renal anemia may not only be treated with ESA therapy but also with appropriate iron supplementation and the improvement of anemia associated with chronic disease, which is associated with inflammation, and inadequate dialysis, another major cause of renal anemia. In Japanese HD patients, Hb levels following hemodialysis rise considerably above their previous levels because of ultrafiltration-induced hemoconcentration; and (ii) as noted in the 2004 guidelines, although 10 to 11 g/dL was optimal for long-term prognosis if the Hb level prior to the hemodialysis session in an HD patient had been established at the target level, it has been reported that, based on data accumulated on Japanese PD and ND patients, higher levels have a cardiac or renal function protective effect, on patients without serious cardiovascular disease,without any safety issues.. Accordingly, the guidelines establish a target Hb level in PD and ND patients of 11 g/dL or more, and recommend 13 g/dL as the criterion for dose reduction/withdrawal. If the serum ferritin is <100 ng/mL and the transferrin saturation rate (TSAT) is <20%, then the criteria for iron supplementation will be met; if only one of these criteria is met, then iron supplementation should be considered unnecessary [223]. Italian Society of Nephrology in its guidelines for the treatment of anemia in chronic renal failure supports that before beginning epoetin treatment, it is essential to evaluate the level of anemia by the measuring Hb concentration, Red blood cell indices (MCV, MCH, MCHC), Reticulocyte count, Iron stores and availability and C-reactive protein (CRP). The minimum target Hb concentration to be attained is 11 g/dL. The upper limit is established individually on a clinical basis. Pending further data, it is advisable to maintain and not exceed 12 g/dL for patients with cardiovascular disease, diabetes, and graft access. In the presence of adequate reserves of iron the need for higher dosages of epoetin define a state of resistance [224].
\n\t\t\t\tIron deficiency (60%) measured by ferritin levels and TSAT at start of dialysis was found in Predialysis Survey on Anemia Management (21 European countries, Israel and South Africa) despite the majority of patients under nephrologist’s care for more than twelve months. Only 27% of patients had started epoetin treatment before dialysis therapy. Thirteen percent had started dialysis therapy first, 33% had started epoetin and dialysis therapy simultaneously, and 28% had not been administered epoetin at any time (total n = 4,095).
\n\t\t\t\t[225] Difference in hemoglobin levels was found in DOPPS study and mean Hgb levels were 12 g/dL in Sweden; 11.6 to 11.7 g/dL in the United States, Spain, Belgium, and Canada; 11.1 to 11.5 g/dL in Australia/New Zealand, Germany, Italy, the United Kingdom, and France; and 10.1 g/dL in Japan. Hgb levels were substantially lower for new patients with end-stage renal disease, and EPO use before ESRD ranged from 27% (United States) to 65% (Sweden) [21].
\n\t\t\t\tAt present, there is a "grey zone" also between the intervention threshold of Hb< 9 g/dl and an Hb level > 13 g/dl, at which CKD is associated with a higher risk of cardiovascular events. It seems to be clearly evident that ESA activate platelets directly and indirectly, and that pathologically extended bleeding time is normalized when an Hb level of 10 g/dl is reached; from the hemostaseological perspective, a threshold level for treatment of renal anemia with ESA is thus defined. According to the present state of knowledge, an Hb target range of 10-11 g/dl seems reasonable for renal anemia; this is also compatible with current recommendations by ESA producers and the Food and Drug Administration (FDA) [226]. This target range avoids the upper and lower risk levels for Hb, and probably ensures a positive ESA effect on quality of life; it is much more cost-efficient than the target range of 11-12 g/dl recommended by the Kidney Disease Outcomes Quality Initiative (KDOQI) in 2007 [227]. ESA treatment for renal anemia should be aimed at reducing transfusion risk, with a treatment target in most patients of 10-12 g/dl; therapy should be individualized, rapid increases in Hb level should probably be avoided, and lowest appropriate ESA doses should be used. Temptation to increase ESA doses to very high levels in an attempt to overcome ESA hypo responsiveness should be resisted [219]. It seems that greater hemoglobin variability is independently associated with higher mortality [228]. Variability caused by laboratory assays, biological factors, and therapeutic response determines patient Hb level variability. Improving factors that can be manipulated (e.g., standardizing EPO and iron algorithms) and adjustment of the target Hb level range, specifically, by increasing the upper bound, likely will decrease the observed variability and further enhance the quality of anemia management [229, 230].
\n\t\t\tIt is obvious that renal anemia in hemodialysis patients remain a serious problem. This was greater before EPO era, when blood transfusion was the only therapeutic approach. Insufficiency of iron and EPO are the most important causes of this anemia. Nowadays with the availability of new I.V. iron supplementation and ESAs this problem became more manageable. The high cost of the EPO treatment makes the iron therapy essential in order to maximize EPO administration result with the lower dose. The ideal hemoglobin target has to be established despite the numerous trials worldwide, and the treatment has to be individualized.
\n\t\tNoninvasive parathyroid imaging studies include technetium (99mTc) sestamibi scintigraphy, ultrasonography (US), computed tomography (CT) scanning, magnetic resonance imaging (MRI) and positron emission tomography (PET). Parathyroid glands need to be examined in case of a diagnosed hyperparathyroidism as a part of preoperative localization of the abnormal glands. Hyperparathyroidism is characterized by elevated parathyroid hormone (PTH) levels in the blood. Due to the underlying cause, it can be divided into primary and secondary. The primary hyperparathyroidism (PHPT) is due to excessive production of PTH from one or more abnormal parathyroid glands. Secondary hyperparathyroidism (SHPT) is a result of hypocalcemia caused by other concomitant diseases (end stage kidney renal disease, etc.). In SHPT usually more than one parathyroid glands are affected. Considered rare disease in the past, the incidence of PHPT has changed dramatically during the last 30 years with the introduction of routine calcium measurements in clinical practice, and is now considered to be approximately 42 per 100,000 persons. Women are affected more frequently than men, in a ratio of approximately 3:1. PHPT occurs predominantly in individuals in their middle years with a peak incidence between ages 50 and 60 years and can reach 4 cases per 1000 persons in women after their 60s. At the time of diagnosis, most patients with PHPT do not have classic symptoms like osteitis fibrosa cystica, nephrocalcinosis, nephrolithiasis or other signs associated with the disease. Symptomatic PHPT is now exception rather than the rule, with more than three-fourths of patients having no symptoms making detected changes of the blood values of calcium, phosphorus and parathyroid hormone (PTH) to be the only reason for diagnosis [1, 2]. By far, the most common lesion found in patients with PHPT is the solitary parathyroid adenoma, occurring in 85–90% of patients, while in the rest 10–15% primary hyperplasia of the parathyroid glands is present [3]. In the past the standard surgical approach for PHPT was the bilateral four-gland parathyroid exploration with the removal of each gland which showed changes macroscopically. While in most of the patients with PHPT only one parathyroid gland is being affected, the above mentioned surgical approach is inappropriate in all cases. Unilateral approaches are appealing in a disease in which only a single gland is involved. So nowadays, the currently most widely used surgical approach is the minimally invasive parathyroidectomy which is connected with less postsurgical complications and shortens the time of operation [4]. To be successful this procedure needs to rely on a precise preoperative localization of the abnormal parathyroid glands. That is, why preoperative parathyroid imaging gained so large importance. The rationale for locating abnormal parathyroid glands prior to surgery is that they can be notoriously unpredictable in their location.
Parathyroid glands differ in shape and size. Typically four glands are present and are located adjacent to the dorsal surface of the thyroid lobes-two upper and two lower pairs. Normal glands tend to be flat and oval and normal measurements are 3 × 5 × 7 mm [5]. The combined weight of all parathyroid glans is 90–130 mg and the superior glands are smaller than the inferior [6, 7]. Autopsy series demonstrate that four glands are found in 91% in subjects, five glands in 4%, and three glands in 5% [8]. Approximately 5% of humans have supernumerary (more than four) parathyroid glands [9]. Supernumerary glands are most commonly found within the thymus. Although gland distribution may deviate widely, the superior parathyroid glands, originating from the fourth pharyngeal pouch, are commonly found along the posterior surface of the upper two-thirds of the thyroid gland (92%). The inferior parathyroid glands have a more variable distribution than the superior ones. They originate from the third pharyngeal pouch together with the thymus. They migrate caudally until they reach the lower pole of the thyroid gland and 17% of them touch the inferior border of the thyroid gland, 26% are within the superior horn of the thymus, and 2% are in the mediastinal thymus [10]. The variable anatomic distribution makes the inferior glands more difficult to locate than the superior ones. Histologically parathyroid glands are made of chief, oxyphillic and transient oxyphillic cells mixed with fat tissue. Chief cells produce PTH. The oxyphillic cells which are rich of mitochondria are with poorly defined function [11].
The normal parathyroid glands cannot be visualized. The lack of the perfect imaging method for precise localization of parathyroid adenomas had led to search for an alternative imaging techniques. Ultrasonography (US) is one of the most widely used procedures. Because of the great anatomic variations of the parathyroid glands, their small sizes, the presence of more than one abnormal gland and the higher frequency of concomitant morphological changes of the thyroid gland, US proved to be specific but with low sensitivity. The success of US is highly operator dependent [12]. Rapid spiral thin-slice CT scanning of the neck and mediastinum with evaluation of axial, coronal and sagittal views can add much to the search for elusive parathyroid tissue [13]. MRI can also identify abnormal parathyroid tissue, but it is time consuming and expensive. It is also less sensitive than other modalities. It can nonetheless be useful when the search with the other noninvasive approaches has been unsuccessful. PET/CT can be used, but like MRI, it is expensive and does not have the kind of experiential basis that make it attractive. There are limiting data for using PET/CT in parathyroid imaging. PET with 18F-fluorodeoxyglucose (18F-FDG) was used with varying success. One study showed that 18F-FDG РЕТ was more sensitive but less specific than 99mTc-sestamibi SPECT [14]. Others reported very low sensitivity for detecting abnormal parathyroid glands [15]. Using РЕТ with 11C-methionine in parathyroid examination has been studied in some patients but because of the very short half-life of 11C-methionine, only 20 min its use is limited only to nuclear medicine centers located near to a cyclotron. There is a general consensus that the most sensitive and specific imaging modality, especially when it is combined with single-photon emission CT (SPECT) is the scintigraphy with 99mTc-sestamibi or 99mTc-tetrofosmin.
Historically, the success of scintigraphy had been compromised by the failure of finding a pharmaceutical agent with specific topic accumulation in parathyroid glands and their close proximity to the thyroid gland. That is why to find a reliable method to differentiate both glands on scintigraphy was crucial. This was first achieved by a combined use of two radionuclides with different uptake in the thyroid and parathyroid cells. The latter allowed to perform a subtraction of the obtained images of both glands and to visualize only the abnormal parathyroid gland, but this proved to be time consuming and with greate radiation exposure to the patients. The first widely used radionuclide for detecting hyperfunctioning parathyroid glands during the 80s was 201Thallium chloride (201Tl). 201Tl chloride accumulates equally in thyroid and parathyroid cells. To make differentiation possible, its application was followed by an injection of 99mTc pertechnetate, with predominant thyroid uptake. Then 99mTc pertechnetate thyroid images were digitally subtracted from the images obtained with 201Tl chloride to allow visualization only of the parathyroid glands [16].
Introduced in clinical practice by Coakley et al. [17], the 99mTc-sestamibi scintigraphy significantly increased the role of preoperative scintigraphy in patients with hyperparathyroidism. Firstly used as a cardiotropic agent this radionuclide showed increased accumulation in a variety of benign and malignant tumors. 99mTc-sestamibi consists of lipophilic cationic molecules. After being intravenously injected these molecules distribute throughout the body accordingly to the local blood supply and by passive diffusion through cell’s membrane accumulate intracellularly into the mitochondria [18, 19]. Normally 99mTc-sestamibi distributes in parotid and submandibular salivary glands, thyroid gland, the heart and the liver, but not in normal parathyroid glands. Visualization of parathyroid adenomas and hyperplastic parathyroid glands depends on the presence of oxyphillic cells, which are rich of mitochondria. The cells of parathyroid adenomas have plenty of mitochondria [20], while the normal parathyroid cells do not [21]. The highest rates of uptake of 99mTc-sestamibi are seen in the solitary adenomas of the parathyroid glands [22]. Not only the amount of intracellular mitochondria is important but also the quantity of oxyphillic cells in the tumors. If the percentage of oxyphillic cells exceeded 25%, accumulation of 99mTc-sestamibi was observed in 78% of parathyroid adenomas. Also false negative results are possible if the oxyphillic cells do not content sufficient amount of mitochondria [23]. Accumulation of 99mTc-sestamibi into the cells also can be influenced by their metabolic activity, the weight and the size of the tumor. This new radionuclide rapidly replaced 201Tl chloride because it showed better quality of the images and higher sensitivity for detecting abnormal parathyroid glands, with less radiation exposure [24].
99mTc-tetrofosmin another myocardial perfusion agent was also used for visualizing parathyroid glands in scintigraphy, but the data for its use so far are limited. 99mTc-tetrofosmin shows some similarities with 99mTc-sestamibi although the way of accumulation is different and it is retained mainly in the cytosol rather than in the mitochondria of the target cells. When used for parathyroid scintigraphy 99mTc-tetrofosmin shows slower washout from the thyroid gland, which makes it unsuitable for single-isotope dual-phase scintigraphy [25]. Nevertheless its sensitivity increases when used in combination with SPECT. Several studies [26, 27] of the diagnostic value of 99mTc-tetrofosmin scintigraphy for topic localization of the hyperfunctioning parathyroid glands in patients with PHPT, showed that this method was useful for the clinical practice and that the accumulation of 99mTc-tetrofosmin depends on the weight of the tumor and the level of PTH.
Generally three protocols are most widely used: single-phase dual-isotope subtraction, dual-phase single-isotope and combination of both [28].
In single-phase dual-isotope modality two types of radiopharmaceuticals with different organ uptake are used. One isotope (99mTc-sestamibi or 99mTc-tetrofosmin) with equal thyroid and parathyroid glands accumulation and another (123I or 99mTc-pertechnetate) with predominant uptake in the thyroid gland are applied consecutively. The obtained images are digitally subtracted and if there is a residual radionuclide accumulation on the subtracted images a hyperfunctioning parathyroid gland can be suspected [28]. Disadvantages of this method are the use of two radionuclides, the necessity of full collaboration from the patient’s side to stay calm and motionless during the examination and the need of very precise positioning of the patient. In addition there is an increase possibility for the presence of artifacts on the subtracted images [29, 30].
The rationale of the single-isotope protocol is based upon the different washout periods of the radionuclide from the thyroid and parathyroid glands. In this method, after an injection of a single radionuclide, early (at 10–15 min) and late (at 1.5–3 h) images are obtained [28].
There are a very few studies directly comparing the results from single-isotope dual-phase modality with single-phase dual-isotope subtractional scintigraphy and the results are inconclusive [31, 32]. So far there is no clear confirmed advantages of one type over another.
No preliminary preparation of the patients before performing single isotope dual-phase scintigraphy is necessary. In subtractional modality some preliminary conditions should be followed such as: discontinuation of Levothyroxine or Iodine containing drugs minimum 20 days before the examination. A case history of every patient about the duration of the disease, any concomitant diseases and medications, especially drugs that could possibly interfere with the calcium-phosphate homeostasis, and family history should be taken.
99mTc-sestamibi and 99mTc-tetrofosmin: they are applied intravenously from 740 to 1110 MBq (20–30 mCi).
99mTc-pertechnetate has a half-life of 6 h and possesses energy of 140 keV. It is used for visualization of the thyroid gland because it accumulates in a functioning thyroid cells. Intravenously 99mTc-pertechnetate is applied form 74–350 MBq (2–10 mCi).
99mTc-sestamibi accumulates in the thyroid and parathyroid glands, but the washout time from both glands differs, showing faster disappearing from the thyroid and retention in parathyroid cells. This allows successful visualization of pathologically changed parathyroid glands on the obtained later images—1.5–2 h after the injection of the radionuclide. This different retention time in both glands may be related to some down-regulation of the P-glycoprotein system in parathyroid adenomas, which delays washout of the nuclide [33]. Just the opposite, in parathyroid hyperplasia these so-called multidrug-related resistance molecules can be upregulated and can cause faster washout of 99mTc-sestamibi and lead to false negative results [34, 35].
To avoid this disadvantage and to improve sensitivity and specificity, the use of single-isotope dual phase (early and late) scintigraphy, based upon the suggestion that 99mTc-sestamibi is washed out faster from the thyroid gland than from the hyperfunctioning parathyroid cells, is recommended [36]. This single-isotope dual phase scintigraphy gained popularity due to its convenience. The fact that 99mTc-sestamibi can also be accumulated in solitary thyroid nodules diminishes the specificity of this procedure, especially in areas with higher incidence of nodular goiter [37, 38]. Some parathyroid adenomas also show rapid washout of 99mTc-sestamibi and make their visualization difficult by this procedure [39]. This led to an introduction of a modified protocol for subtractional scintigraphy by adding a second radionuclide with a preferential accumulation in the thyroid tissue.
99mTc-sestamibi scintigraphy is generally regarded to be the most sensitive and specific imaging modality especially when it is combined with other imaging procedures. The combination of US examination with dual-isotope 99mTc pertechnetate/99mTc-sestamibi scintigraphy for preoperative localization of parathyroid adenomas leads to visualizing of the parathyroid adenomas in 95.2% of the cases (20 patients out of 21). Reaching such high diagnostic precision allows to minimize the extent of the surgical procedure and gives way to apply routinely and successfully minimally invasive parathyroidectomy only of the pathologically changed glands [40, 41].
Comparing different imaging methods,99mTc-sestamibi scintigraphy has higher sensitivity and specificity than US and CT in discovering adenomas of the parathyroid glands. With regards to the hyperplasia of the parathyroid glands 99mTc-sestamibi scintigraphy shows to be of less value [42, 43]. Hyperplastic parathyroid glands are visualized in 10–62.5% of the cases [44, 45]. In multiple endocrine neoplasia syndrome (MEN), where hyperplasia of the parathyroid glands is common, only 55% of the abnormal glands are seen on 99mTc-sestamibi scintigraphy [42, 46, 47]. 99mTc-sestamibi scintigraphy shows to be highly effective in discovering ectopic hyperfunctioning parathyroid glands, which in some studies, are observed in approximately 20% of the cases with PHPT and represent a diagnostic and therapeutic challenge [48]. Visualizing small parathyroid adenomas represents a specific problem. One study showed, that in surgically removed adenomas weighted less than 0.5 g, preoperative US was negative, but 99mTc-sestamibi scintigraphy discovered adenomas in 87% of cases and the combination with SPECT increased sensitivity to 95% [21].
In patients with SHPT, seems to have a direct correlation between 99mTc-sestamibi uptake with the blood level of parathyroid hormone and the phase of the cells’ cycles [49]. The lowest level of accumulation corresponds to G(0) phase and the highest to phase G(2) + S. No such correlation with the weight of the glands is found [49]. The fixation of the radionuclide depends on the functional status of the tissues, i.e., increased accumulation accompanies the cells’ active growing phase or is directly connected to the state of autonomy of the parathyroid cells [46].
The reason why not all pathologically changed parathyroid glands accumulate radionuclide remains unclear. This may be due to the different degree of activity and proliferation of the cells of the parathyroid adenomas. It was suggested that there is a relationship between nuclide accumulation and the degree of autonomy of the cells of the adenoma, i.e., the loss of the suppressive effect of calcium upon the secretion of the parathyroid hormone. The cells of the parathyroid adenomas and these of the hyperplastic glands show higher threshold for calcium suppression or have no threshold at all in comparison with the normal parathyroid cells. Due to this fact, these cells secrete more PTH for any given blood calcium level, show higher metabolic rate and capability to accumulate more 99mTc-sestamibi. Hyperplastic parathyroid glands are to some extent with preserved functional regulation, respond to the normal suppressive stimuluses, have lower metabolic rate and accumulate less of the radionuclide.
Due to its higher affinity to the parathyroid adenomas, 99mTc-sestamibi scintigraphy was used in cases of relapse of the hyperparathyroidism after parathyroidectomy or after autotransplantation of parathyroid glands.
Nowadays, there are several imaging methods for discovering hyperplastic parathyroid glands. The results so far are inconclusive. The dual-phase 99mTc-sestamibi scintigraphy in preoperative localization of the hyperplastic parathyroid glands in patients with profound secondary hyperparathyroidism do not show high sensitivity, but is of help to discriminate between patients with nodular and diffuse hyperplasia [50].
The role of 99mTc-sestamibi scintigraphy in patients with end-stage renal disease and secondary hyperparathyroidism is still unclear. The uptake of 99mTc-sestamibi can be suppressed by the use of calcitriol in these patients. In one study [51] 99mTc-sestamibi scintigraphy managed to visualize 1 or more (maximum 3) parathyroid glands in most, but not in all patients on hemodialysis with PHT levels above 600 pg/ml. Performing suppressive test with calcitriol (2 mg of calcitriol applied i.v. after each hemodialysis for two consecutive weeks) showed suppression of 99mTc-sestamibi uptake at least in one parathyroid gland in 57% of the cases and full suppression in all glands in 36%. The basal level of PHT or its lowering after this test showed to be of no predictive value for the suppression of 99mTc-sestamibi uptake in the parathyroid glands. Because of its lower sensitivity, the 99mTc-sestamibi scintigraphy was found to be of limited value in preoperative evaluation in uremic patients with secondary hyperparathyroidism, but its significance grew up in localizing hyperfunctioning glands left after the first operation [51].
Single-isotope dual phase 99mTc-sestamibi scintigraphy is easily performed, and needs only application of 99mTc-sestamibi. After injection of the radiopharmaceutical, early (10–15 min), and late planar (1,5–3 h) images are obtained (Figures 1 and 2).
Single-isotope dual-phase scintigraphy with 99mTc-sestamibi. The late image (120 min) shows a focus of a residual activity (arrow), caudally of the right thyroid lobe consistent with adenoma of the right lower parathyroid gland.
Single-isotope dual-phase scintigraphy with 99mTc-sestamibi. On the early images (20 min) relatively diffuse uptake in the area of the thyroid gland and a focus of increased accumulation of the radionuclide (thin arrow), caudally of the left thyroid lobe are seen. On the late phase images (120 min) only a focus of a residual activity (thick arrow), caudally of the left thyroid lobe is visualized-suggesting adenoma of the lower left parathyroid gland.
In some cases, the obtained early and late images show no signs of abnormal accumulation of radionuclide, but when combined with SPECT, than adenomas located at the back of the thyroid gland become visible (Figure 3a and b).
(a) Single-isotope dual-phase scintigraphy with 99mTc-sestamibi. Early planar images show diffuse uptake in the thyroid gland. Late planar images show no sign of a focus of residual activity in the neck area or mediastinum. (b) (The same patient) 99mTc-sestamibi SPECT images show an area of a residual activity, located dorsally and caudally of the left thyroid lobe (arrows) suspicious for a parathyroid adenoma.
So, the combination of a single-isotope dual-phase scintigraphy with 99mTc-sestamibi with SPECT can be of great help.
During many years in the past, two-dimensional images have been obtained, mainly AP-images, and rarely this was combined with lateral and oblique images [52, 53].
SPECT has gained more importance, because it gives three-dimensional images. There are accumulating data from the literature, that it improves sensitivity for discovering and localizing the hyperfunctioning parathyroid glands [54, 55]. The main reason for this is the improved contrast resolution of SPECT (Figure 4).
Early 99mTc-sestamibi SPECT images showing an area of radionuclide accumulation (arrows), located dorsally and caudally of the left thyroid lobe.
99mTc-tetrofosmin, another myocardial perfusion agent, is also used for parathyroid scintigraphy, but there are limited data in the literature for its use. Several studies [26, 27] assess the diagnostic value of 99mTc-tetrofosmin scintigraphy for topic localization of the hyperfunctioning parathyroid glands in patients with PHPT. They show that this method was useful for the clinical practice and that the accumulation of 99mTc-tetrofosmin depended on the weight of the tumor and the level of PTH. The early images (15th min) prove to be better than the late ones (120th min). 99mTc-tetrofosmin is washed out more slowly from the thyroid gland than 99mTc-sestamibi but both radionuclides give better results in comparison with 99mTc-pertechnetate/201Tl-substractional technique [56]. 99mTc-tetrofosmin looks promising alternative of 99mTc-sestamibi with similar properties and capabilities of localizing parathyroid adenomas.
Dual-isotope substractional scintigraphy with 99mTc-tetrofosmin/99mTc-pertechnetate and SPECT represent highly sensitive method for localization of parathyroid adenomas and their combination can further improve the diagnostic precision [57]. 99mTc-tetrofosmin, like 99mTc-sestamibi is not perfect for localization of hyperplastic parathyroid glands in patients with SHPT, because of its lower sensitivity [56]. 99mTc-tetrofosmin has some similarities with 99mTc-sestamibi, but its mechanism of accumulation in the cells is different. In contrast with 99mTc-sestamibi, which accumulation depends on mitochondria’s membrane potential, retention of 99mTc-tetrofosmin depends mainly on cell’s membrane potential [25]. 99mTc-tetrofosmin, shows slower wash out from the thyroid on the late planar images (120 min). This leads to the necessity to obtain additional later planar images—between 150 and 160 min. This slower wash out makes 99mTc-tetrofosmin to be unsuitable for performing single-isotope, dual-phase scintigraphy [25]. To avoid misleading, because of prolonged retention of the radiopharmaceutical in the thyroid adenomas, an US examination should be performed, especially in iodine deficient areas [56].
Figure 5 is presented a single-isotope dual-phase scintigraphy with 99mTc-tetrofosmin, combined with SPECT in a patient with PHPT.
(a) Early phase image (20 min) shows an intense uptake of the radionuclide at the lower part of the right thyroid lobe, which activity is still present on the late image (120 min) (arrows) and (b) (same patient) SPECT images showing an intense uptake dorsally and caudally of the right thyroid lob (arrow), suggestive for adenoma of the right lower parathyroid gland.
In 99mTc-tetrofosmin scintigraphy early images at 20th min show better quality than the later ones at 120th min (Figure 6a–c).
(a) Single-isotope dual-phase scintigraphy with 99mTc-tetrofosmin. Early planar images (20 min) are with better quality, (b) (same patient) single-isotope dual-phase scintigraphy with 99mTc-tetrofosmin and (c) 99mTc-tetrofosmin SPECT images—an area (arroes) with high uptake located dorsally of the lower right lobe is seen, consistent with adenoma of the right lower parathyroid gland.
Late planar images (120 min)—negative scan.
In this case, early SPECT gives opportunity to visualize adenomas, which were not seen on the late planar images, which is probably due to the rapid wash out of the radiopharmaceutical from some adenomas, as well as to the small sizes of the adenomas. When combined with SPECT, dual-phase scintigraphy with 99mTc-tetrofosmin can detect adenomas with rapid wash out of the radiopharmaceuticals.
Pearls/pitfalls:
The single isotope dual-phase scintigraphy with 99mTc-sestamibi or 99mTc-tetrofosmin could miss parathyroid adenomas with rapid washout of the radionuclide. The combination with early SPECT improves sensitivity.
The single isotope dual-phase scintigraphy with 99mTc-tetrofosmin in patients with PHPT and SHPT is with less sensitivity and specificity, because of the poor quality of the obtained images and slower washout of the radionuclide from the thyroid gland.
SPECT combined with single-isotope scintigraphy and subtractional methods for visualization of hyperfunctioning parathyroid adenomas in patients with PHPT and SHPT is a reliable additional modality. It does not cause additional and unnecessary exposure of the patients to the gamma-rays and can increase sensitivity.
The rationale that stands behind dual-isotope subtractional scintigraphy with 99mTc-pertehnetat/99mTc sestamibi, is that 99mTc-sestamibi accumulates in both, thyroid gland and hyperfunctioning parathyroid glands, while 99mTc-pertechnetate uptakes only in the thyroid. First thyroid specific radionuclide 99mTc-pertechnetate is injected and at 30th min images are obtained. Afterwards, while the patient is still under the detector, second radionuclide 99mTc sestamibi with dual accumulation is applied and a second set of images on the 20th min are obtained. Later images are subtracted digitally from the first set of images and if a focus of residual activity on the subtractional images is detected, a hyperfunctioning parathyroid gland is supposed. The combination with early SPECT can improve sensitivity (Figure 7a and b).
(а) Dual-isotope subtractional scintigraphy with 99mTc-pertehnetat/99mTc sestamibi. Upper image on the left-image of thyroid gland obtained with 99mTc-pertehnetat. Upper image on the right an image obtained with 99mTc sestamibi (arrow). Lower image. Subtractional image showing a focus of a residual activity (arrow) in upper back part of the left thyroid lobe consistent with left parathyroid adenoma and (b) (same patient) dual-isotope subtractional scintigraphy with 99mTc-pertehnetat/99mTc sestamibi. Early SPECT images showing an area of intense uptake located dorsally and cranially of the left thyroid lobe.
The subtraction could be of help, when the patients had undergone surgery of the thyroid, but some thyroid parenchyma is still present. This method is important in the presence of more than one abnormal parathyroid gland.
Dual-isotope subtractional scintigraphy with 99mTc-pertehnetat/99mTc sestamibi combined with SPECT in a 51 years old man with MEN-type 1 syndrome—pheochromocytoma, parathyroid adenoma and prolactinoma, who had previously undergone thyroid (subtotal thyroidectomy) and parathyroid (left upper parathyroid gland) surgery. Subtractional images (Figure 8a) and early SPECT images (Figure 8b) show two areas of intense uptake located below the remnants of the both thyroid lobes. SPECT images show that the lesion below the right thyroid lobe was located also adjacent to the back part of the right thyroid lobe.
(а) Dual-isotope subtractional scintigraphy with 99mTc-pertehnetat/99mTc sestamibi. Subtractional image showing two areas of intense uptake consistent with two parathyroid adenomas and (b) SPECT images showing an area of intense uptake located dorsally and caudally of the right thyroid lobe.
In some cases, obtaining late images could also be of help. Combining dual-isotope, 99mTc-pertehnetat/99mTc sestamibi, subtractional scintigraphy with SPECT, and also recording late planar images on the 120th min (late phase) would improve sensitivity (Figures 9 and 10).
(а) Dual-isotope subtractional scintigraphy with 99mTc-pertehnetat/99mTc sestamibi. Subtractional image showing no residual activity in the areas of the neck and chest and (b) late planar images showing a residual activity (arrow) in the middle of the left thyroid lobe, consistent with left parathyroid adenoma.
(а) Dual-isotope subtractional method with 99mTc-pertehnetat/99mTc-tetrofosmin. The upper row: on the left image of the thyroid gland with 99mTc-pertehnetat and on the right image of the parathyroid gland with 99mTc-tetrofosmin (arrow). The lower row shows subtractional image representing adenoma of left parathyroid gland and (b) dual-isotope subtractional method with 99mTc-pertehnetat/99mTc-tetrofosmin early SPECT images showing an area of hyper fixation, located caudally of the left thyroid lobe.
Pearls/pitfalls
Dual isotope subtractional scintigraphy with 99mTc-pertehnetat/99mTc sestamibi or 99mTc-pertehnetat/99mTc-tetrofosmin allows visualization of abnormal parathyroid glands after subtraction is performed, even on the early obtained images. This helps to shorten the time of examination to 80–90 min and is of great use in the postsurgical follow up and when more than one abnormal gland is present.
Disadvantages of the subtractional scintigraphy with 99mTc-pertehnetat/99mTc sestamibi or 99mTc-pertehnetat/99mTc-tetrofosmin are: necessity of applying of two radionuclides, the need of very precise positioning of the patients in this dual phase method requiring full collaboration from patient’s side and the probability of the presence of artifacts in the obtained images.
Secondary hyperparathyroidism is characterized with hyperplasia of parathyroid glands, because it is caused by longstanding uncontrolled hypocalcemia, which leads to a profound overstimulation of a previously normal parathyroid glands. Over time this overstimulation causes hyperplasia and eventually adenomatous changes (tertiary hyperparathyroidism) of the parathyroid glands with PTH levels far more exceeding those observed in PHPT (Figure 11). Nevertheless, hyperplastic parathyroid glands usually show faster wash out of the radionuclides in comparison to solitary adenomas, which makes them more difficult to be visualized with scintigraphy (Figure 12). Negative scans, may be associated with the possible suppression of the accumulation of radiopharmaceuticals in the parathyroid cells as a result of the concomitant calcitriol intake. The use of calcium channel blockers may affect the uptake of 99mTc-sestamibi by parathyroid cells and reduce the sensitivity of the method. A study found that negative scans are twice as likely in patients taking calcium antagonists than those who do not take these medications (OR2, 88.95% CI, 1.03–8.10, p 0.045) [58]. So, adding the poor general condition of the patients, pathologically changed parathyroid glands are more difficult to be localized in SHPT than in PHPT.
Single-isotope, dual-phase scintigraphy with 99mTc-sestamibi in a patient with secondary hyperparathyroidism. The late phase (120 min) show a focus of residual activity (arrow)—consistent with parathyroid adenoma (probably tertiary hyperparathyroidism).
(а) Single-isotope, dual-phase scintigraphy with 99mTc-tetrofosmin in a patient with secondary hyperparathyroidism. Early (20 min) and late (120 min) images show no focus of a residual activity in the area of neck and mediastinum and (b) (same patient) early SPECT images showing an area of nuclide accumulation caudally of the left thyroid lobe, suspicious for parathyroid adenoma.
The visualization of abnormal parathyroid glands is difficult due to their variations in number and localization. Noninvasive parathyroid imaging studies include 99mTc-sestamibi scintigraphy, ultrasonography, computed tomography scanning, magnetic resonance imaging, and positron emission tomography. There is a general consensus that the most sensitive and specific imaging modality is the scintigraphy with 99mTc-sestamibi or 99mTc-tetrofosmin. 99mTc-sestamibi scintigraphy significantly increases the role of preoperative scintigraphy in patients with hyperparathyroidism and allows unilateral surgical approach with minimally invasive parathyroidectomy to be used. Generally three protocols with the use of two radiopharmaceuticals, 99mTc-sestamibi or 99mTc-tetrofosmin, are most widely applied: single-phase dual-isotope subtraction, dual-phase single-isotope and combination of both. Each one of them has specific advantages and disadvantages. While, single parathyroid adenomas are localized with greater precision, hyperfunctioning parathyroid hyperplastic cells represent a real challenge to the imaging modalities.
Several factors can influence the radionuclide uptake in pathologically changed parathyroid cells:
biochemical factors
Total calcium levels—higher preoperative calcium levels are more frequently seen in patients with positive scans.
Parathyroid hormone levels.
A significant correlation between radiopharmaceutical uptake and preoperative levels of PTH is observed. As higher PTH is, as higher is the possibility for positive scans.
Vitamin D levels.
Patents with vitamin D deficiency are more likely to have positive scans.
Suboptimal levels of vitamin D, can stimulate the growth of the parathyroid adenomas independently from hypocalcemia and 1,25-dihydroxyvitamin D3 deficit can change the set-point of calcium suppressive effect upon PTH secretion [59].
Calcium-channel blockers.
The use of calcium-channel blockers can influence the uptake of the radiopharmaceutical in the parathyroid cells diminishing the sensitivity of the method.
biological factors
Size—although considered to be very important, it is not the only determining factor.
Type of cells of the parathyroid adenoma—because oxyphilic cells contain more mitochondria, they uptake radionuclides to a larger extent.
P glycoprotein and MDR gene products.
Uptake of 99mТс-sestamibi and 99mТс-tetrofosmin in the cells of the parathyroid adenomas depends on the activity of the P glycoprotein coded by MDR gene, which is functioning as an ATP dependent efflux pump, protecting against accumulation of lipophilic cationic radiopharmaceuticals, including 99mТс-tetrofosmin [60]. The expression of P glycoprotein in the parathyroid adenomas appears to be important factor determining radiopharmaceutical uptake. In one study 71% (10 out of 14) of adenomas with high P glycoprotein membrane activity have shown negative scans, 70% (45 out of 64) with negative P glycoprotein expression (р = 0.006) have shown positive scans [61].
Supporting women in scientific research and encouraging more women to pursue careers in STEM fields has been an issue on the global agenda for many years. But there is still much to be done. And IntechOpen wants to help.
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