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Agnieszka ZAporA-KurelMarta rydZewsKAMaciej edward MałyszkoAdrianna ZAjKowsKANatalia Anna drobeKjolanta Małyszko

2nd department of Nephrology and Hypertension with dialysis unit, Medical university of bialystok

Additional key words:diabetic kidney diseaseanemiairontreatment

Dodatkowe słowa kluczowe: cukrzycowa choroba nerekniedokrwistośćżelazoleczenie

Address for correspondence:2nd department of Nephrology and Hypertension with dialysis unitMedical university15-276 bialystok, M. sklodowskiej-Curie 24apolandtel: 48858317872, fax: 48858317870e-mail: jolmal@poczta.onet.pljolanta.malyszko@umb.edu.pl

prace pogląDowe

Anemia in diabetic kidney disease - underappreciated but still clinically relevant problem

Niedokrwistość w cukrzycowej chorobie nerek - niedoceniany, ale ciągle aktualny problem kliniczny

Anemia is the most common dis-order of the blood with iron deficiency being the predominant cause. On the other hand, diabetes prevalence is increasing rapidly. Over time, dia-betes can damage the heart, blood vessels, eyes, kidneys, and nerves. Diabetic kidney disease (DKD) may be present in both types 1 and type 2 diabetes mellitus. Anemia is one of the common feature of chronic kidney disease. The epidemiological data on anemia prevalence are limited. In this review data on epidemiology, patho-genesis, complication and treatment of anemia in diabetic kidney disease are presented.

The authors declare that they have no competing interests.

Niedokrwistość jest częstym schorzeniem hematologicznym a nie-dobór żelaza jest jej najczęstszą przy-czyną. Z drugiej strony, częstość wy-stępowania cukrzycy wzrasta istotnie w ostatnich latach. Z czasem trwania cukrzycy pojawiają się powikłania ze strony układu sercowo-naczyniowe-go, narządu wzroku, układu nerwowe-go i nerek. Cukrzycowa choroba ne-rek może występować w obu typach cukrzycy, zarówno w typie 1 jak i 2. Niedokrwistość jest także jednym z objawów przewlekłej choroby nerek Dane epidemiologiczne dotyczące częstości występowania niedokrwi-stości w cukrzycowej chorobie nerek są ograniczone. W pracy przedstawio-no dane dotyczące częstości wystę-powania niedokrwistości, przyczyn, powikłań i jej leczenia w cukrzycowej chorobie nerek.

IntroductionAnemia is the most common disorder

of the blood, affecting about a quarter of the people globally [1]. The name is de-rived from ancient Greek: ἀναιμία anaim-ia, meaning “lack of blood”, from ἀν- an-, “not” + αἷμα haima, “blood”. Anemia is a condition in which circulating the red blood cells count or their lowered ability to car-rying oxygen is too scarce for physiologic needs. Anemia is defined as a reduction hemoglobin concentration (HGb), hema-tocrit (HCT), or number of red blood cells (rbC). In practice low hemoglobin con-centration or a low hematocrit is the most common used. According to world Health organization (wHo) criteria for anemia is respectively in men HGb <13 g/dl and women <12 g/dl [2]. These criteria weren’t created to be used as a gold standard for the anemia diagnosis, it were a part of in-ternational nutrition wHo’s studies [3]. wHo definition of anemia and establish a reference point for anemia is appropriate to apply across populations [4] and nowadays is widely use in clinical practice.

Epidemiology of anaemia in diabetic kidney disease

Iron-deficiency anemia affects nearly 1 billion [5]. A moderate degree of iron-de-ficiency anemia affected approximately 610 million people worldwide or 8.8% of

the population. It is slightly more common in females (9.9%) than males (7.8%) [5]. Mild iron deficiency anemia affects ano-ther 375 million. [5], anemia due to iron deficiency resulted in about 183,000 de-aths – down from 213,000 deaths in 1990. [6] It is more common in females than ma-les, [5] among children, during pregnancy, and in the elderly [1]. Anemia increases costs of medical care and lowers a perso-n’s productivity through a decreased abili-ty to work [7].

diabetic kidney disease (dKd) may be present in both type 1 and type 2 diabetes mellitus. dKd is accompanied by charac-teristic structural changes. The structural changes include, glomerular basement membrane thickening, mesangial expan-sion, glomerular sclerosis and podocyte injury [8-10].The main clinical manifesta-tions of dKd are albuminuria, hematuria and progression in chronic kidney disease, which can be delayed by appropriate treat-ment.

diabetic nephropathy is more preva-lent among certain high risk groups. such as Hispanics, African Americans, Native Americans [11,12] as well as in people of south Asian origin (especially those from bangladesh, bhutan, pakistan, India or sri lanka) [13]. In this communities the rates of diabetes and high blood pressure are high. which, contributes to the higher

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risk of developing diabetic nephropathy and CKd. Also female sex is contributed to higher risk of developing CKd. In dia-betic nephropathy risk of anemia is higher compared with the people with non-diabe-tic kidney disease and it is more severe [14–20]. diabetic patients often develops anemia while theirs serum creatinine is still within the normal range. According to the study by Al Khury et al. [14] anemia is more prevalent even at the earliest stages of CKd [11,12] not only as in others stu-dies have shown that it is more prevalent at stage 2 and 3 CKd [16]. It has been re-ported that around 15-25% of people with diabetes have unrecognized previously anemia [15,18-23]. In addition, in a popula-tion-based sample of people with diabetes a prevalence of previously unrecognized aemia was 15% [24]. The lower prevalen-ce of diabetes in this study may be due to the fact that previous studies have large-ly been performed in patients attending hospital diabetes clinics [15-17, 19,20,22, 23,25]. It should be also stressed that the prevalence of anaemia increases in paral-lel with worsening renal function. patients with an eGFI < 60 ml ⁄ min per 1.73 m2 (stages 3, 4 and 5 chronic kidney disease) in this study accounted for 29% which was in line with another uK population-based study (31%) [21].

Screening of anemia in diabetic kid-ney disease

According to previous studies, a fre-quent complication of diabetic nephropa-thy is anemia. Furthermore, the occur-rence of anemia is earlier in patients with diabetic renal disease than in non-diabetic with chronic kidney disease [26]. At the beginning we will discuss screening of diabetic nephropathy, which is a clini-cal syndrome characterized by persis-tent albuminuria (>300 mg/24 h, or 300 mg/g creatinine), a decline in glomerular filtration rate (GFr), increased arterial blood pressure [27]. Measurement of the albumin:creatinine ratio (usually single early-morning urine sample) allows for di-agnosis of dKd. Abnormal values are dif-ferent by gender: in men 2,5 mg/mmol or more and 3,5 mg/mmol or more in women [27]. KdIGo (Kidney disease: Improving Global outcomes) Clinical practice Guide-line for Anemia in Chronic Kidney disease also use wHo criteria for diagnosis, but at the same time pay attention that ane-mia in CKd, including dKd can indicate on underlying medical problem [28]. The appearance or progression of anemia may be a sign of new problem that is causing by blood loss or involve disrupted the red cell production. Typical CKd anemia is normocytic and normochromic with bone marrow of normal cellularity and not differ from anemia of chronic disease. Accord-ing to KdIGo Guideline anemia connect-ing with CKd is multifactorial and needs wider diagnostics included: complete blood count (CbC), which should include HGb concentration, red cell indices, white blood cell count and differential, platelet count, absolute reticulocyte count, serum

ferritin level, serum transferrin saturation (TsAT), serum vitamin b12 and folate levels [28]. First treated are detectable causes of anemia such as iron deficiency, vitamin b12 and folate or chronic bleed-ing [28].

Pathogenesis and differential dia-gnosis

Anemia in chronic kidney disease is a condition characterised by lower-than-normal concentration of hemoglobin (Hb). The major cause of anemia of CKd is a decrease erythropoietin production due to kidney damage. erythropoietin stimu-lates the bone marrow to produce red blood cells, and it increase production by the kidney is a response to low tissue oxygen levels. The pathogenesis of dKd is multifactoral, and therefore identifying the underlying its cause is necessary to initiating the appropriate treatment and help guide management of these patients. There are several possible mechanisms which may contribute to the occurrence of anemia in diabetic patients. Anemia in patients with diabetic kidney disease (dKd) results mainly from insufficient pro-duction of erythropoietin with inhibition of erythroid progenitor cells formation and inappropriate response of erythropoietin to decreased concentration of Hb [29,30]. possible pathophysiological mechanism of erythropoietin hyporesponsiveness are still discussed, but authors suggest chronic inflammation, microvascular dam-age in the bone marrow, impairment of the tubulointerstitial tissue, an autonomous neuropathy and a variety of other factors [31-33]. Namely, damage to the epo-pro-ducing fibroblasts either through fibrosis or chronic inflammation as well as inter-stitial pathological changes have been de-scribed in diabetic nephropathy and they are more notable in patients with type 2 diabetes [34]. As an alternative, anaemia may be developed secondary to auto-nomic neuropathy which impairs anaemia sensing by the erythropoietin-producing cells of the kidney [15]. lastly, several drugs, predominantly the renin–angioten-sin system inhibitors may decline haemo-globin concentration by 0.2-0.3 g/dl [35-38]. several mechanisms have been proposed for the anemia inducing effects of inhibitors of the renin-Angiotensin-sys-tem. ACe inhibitors decrease the vascular resistance in efferent arterioles, enhance the oxygenation in the peritubular region and as a result decrease the signal for erythropoietin synthesis. The tetrapeptide Ac-sdKp (goralatide), a normal inhibi-tor of the entry of pluripotent stem cells into the s phase, is metabolized by An-giotensin-converting-enzyme. Ac-sdKp, in the presence of an ACe inhibitor, can accumulate and thereby decrease eryth-ropoiesis [39]. These important classes of hypotensive drugs may hence induce or worsen symptomatic anemia in patients with kidney disease [35,40,41]. Addition-ally, there is a growing list of commonly used hypoglycaemic medications impli-cated as factors underlying anaemia. Thi-

azolidinedione’s by increasing the plasma volume, may contribute to anemia due to hemodilution [42,43]. The iron deficiency is common cause of anemia in dKd due to numerous factors i.e. reduced intake and impaired intestinal absorption of dietary iron or chronic inflammation. Iron deficien-cy can be absolute or relative (functional) in nature. Absolute iron deficiency is de-fined by severely reduced or absent iron stores in bone marrow resulting in insuffi-cient iron level to produce Hb. In contrast, functional iron deficiency is characterized by sufficient iron stores, but deficient iron availability for incorporation into erythroid precursors during erythropoiesis. It is usually linked with use of erythropoietin-stimulating agents (esAs) in CKd [42,45]. other causes including nutritional vitamin deficiencies such as folate and b12 are rare in dKd [37].

Anemia in chronic kidney disease and mentioned deficiencies anemias are included to hyporegenaritive anemias de-fined as a reticulocyte count of < 50x109/l. by contrast, regenerative anemias are charcterised by a reticulocyte count of > 100x109/l. This classification based on the measurement of reticulocytes indicates whether anaemia is due to a central defect of red blood cells (rbC) production (i.e. aplastic anemia, deficiencies anemias, anemia in chronic diseases) or to accel-erated destruction (haemolysis, haemor-rhage). The analysis of the complete blood count (CbC), including Hb concentration, red cell indices, white blood cell count and differential, and platelet count is crucial to indicate severity of anemia, function of bone marrow and to initial differentiation of anemia. The most useful markers to dif-ferentiate kind of deficiency are mean cor-puscular volume (MCV) and mean corpus-cular hemoglobin (MCH) values. Folate or vitamin b12 deficiencies may lead to mac-rocytosis and hyperchromia, whereas iron deficiency (and inherited disorders of Hb formation) may present microcytosis with hypochromia [28] Macrocytosis accompa-nied by leukocytosis and thrombocytosis can be observed in folate or vitamin b12 deficiencies as well as in generalized disorder of hematopoiesis caused by tox-ins and myelodysplasia. by contrast, the anemia of CKd is normochromic and nor-mocytic with diminished survival of rbCs. It is, in general, morphologically identical with anemia of chronic disease caused by an inflammation-mediated reduction in rbC production. [46] Abnormalities of the white blood cell count and differ-ential or platelet count are not specific of the anemia of CKd and therefore the further investigation of causes should be indicated in that case. [46,47]. To identify iron deficiencies and distinguish beetwen absolute and functional the measure-ments of serum iron, total iron-binding capacity (TIbC), ferritin, and transferrin saturation (plasma iron concentration di-vided by TIbC x 100) are used commonly. Typically, patients with functional iron deficiency have either normal or elevated serum ferritin concentration (>100 ng/ml

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in non-dialysis dependent patients and >200 ng/ml in hemodialysis dependent patients), but the transferrin saturation is about 20 percent or less. In patients with esA- induced functional iron deficiency the serum ferritin concentration may be as high as 800 ng/ml or even higher. In patients with absolute iron deficiency we observe decreased transferin saturation about 20 percent or less, but the serum concentration of feritin is decreased (<100 ng/ml in non-dialysis dependent patients, <200 ng/ml hemodialysis dependent patients). by comparison, patients with normal renal function and severe iron de-ficiency anemia typically have a serum ferritin concentration <30 ng/ml [48,49].

Complication of anemia in DKDAnemia in dKd increase angiopathy

and cardiovascular morbidity and mortality. In case of diabetic kidney disease, anae-mia develops in its early stage, has higher severity and is related to an increased risk of developing cardiovascular disorders, cerebral stroke and deterioration of renal function. As a result, an increase in the number and duration of hospitalisations as well as mortality rate can be observed [50-53]. Anaemia significantly affects life quality, particularly in patients with diabetic kidney disease [54] as well as decreases physical and mental functions. Also, anae-mia is manifested as malaise, dyspnoea, weakness, appetite and sleep disorders, impairment of cognitive functions and even depressive symptoms. Clinical manifesta-tion of anaemia occurs in advanced stage of renal failure with insufficient blood sup-ply. during the first stage of the disease patients feel no clinical symptoms and adapt to gradual decrease in haemoglobin concentration.

diabetic anemia in kidney disease deteriorates both the course of the dis-ease and prognosis. Individuals suffering from diabetes, chronic kidney disease and anemia constitute a triad of patients with high rate of mortality and cardiovascular complications [55]. long-term anemia in diabetic kidney disease is also a factor contributing to the development of retin-opathy, neuropathy and diabetic foot. The risk of cardiovascular diseases in patients with chronic kidney disease is unrelated to gender, occurs in early stage of renal fail-ure and increases with its progress [56]. Cardiovascular diseases constitute 50% of death causes in patients with end-stage kidney disease. Cardiovascular mortality in dialysed individuals is 10-30-fold higher compared to general population and 100-fold higher in persons over 40 years of age with diabetic kidney disease in stage 5 [57]. Hb concentration decrease by 1g/dl leads to increased risk of left ventricular hypertro-phy by 6%, increased left ventricular mass index, lVMI, by 7-10g/m2 and increased left ventricular volume index, lVVI, by 8ml/m2 every year [58]. deteriorating anemia during kidney disease leads to reduction of peripheral resistance, activation of sympa-thetic system, increased activity of renin-angiotensin-aldosteron system, which af-

fects the release of antidiuretic hormone [59]. This process leads to left ventricular hypertrophy, coronary disease, arrhythmia and sudden cardiac death. 75% of patients starting renal replacement therapy are di-agnosed with left ventricular hypertrophy [60]. This disorder leads to reduced ejection fraction and kidney hypoperfusion which is manifested by a decrease in glomerular fil-tration rate. Haemodynamic changes are accompanied by neurohormonal changes which also affect renal function. Anemia is related to a constantly increased cardiac output and thus affects large vessels lead-ing to their hypertrophy and reconstruction. dialyzed patients show increased arterial stiffness and faster atherosclerosis devel-opment. Anemia treatment in early stage of renal disease decreases the risk of death in dialysis patients [61] and may prevent heart failure in hemodialysis patients with normal left ventricular volume [62]. Nor-malization of hemoglobin concentration in case of circulatory insufficiency class I-II by NyHA may increase the risk of developing cardiovascular diseases [63].

Iron therapy in diabetic kidney dis-ease

early implementation of esA and iron into anemia treatment allows to keep stable hemoglobin concentration in the maintenance stage of esA therapy [64]. The decision on treatment commencement ought to be made individually for each pa-tient with respect to hemoglobin concentra-tion and clinical status. Target hemoglobin concentration depends on patient’s age, physical activity, coexisting disorders and response to the treatment [65]. Hemoglo-bin concentration within 10-12 g/dl in CKd patients is fully sufficient to obtain maximal improvement in the quality of life and to decrease mortality rate [66,67]. Maintain-ing hemoglobin concentration at 10-12 g/dl in diabetic kidney disease is vital since higher hemoglobin concentrations are re-lated to increased risk of death. particu-larly, Hb>13g/dl bears the risk of develop-ing arterial hypertension and thrombosis [28,37,68].

Iron deficiency in patients with chronic kidney disease is a relatively common is-sue. In early stage of renal failure the major goal of the therapy with iron is to manage iron deficiency, which allows to increase hemoglobin concentration without the ne-cessity to include the erythropoiesis stimu-lating factors. As regards esA treated pa-tients, proper iron supplies are necessary to obtain properly stimulated erythropoiesis and facilitate the reduction of esA dose le-ading to a decrease in the risks related to the therapy [28]. In order to obtain proper response to esA, iron supplementation ought to be started prior to esA treatment [28]. According to KdIGo guidelines, iron treatment should be started at ferritin con-centration maximally 500 ug/l and TsAT maximally 30% [28]. european guidelines recommend iron supplementation only when iron parameters are indicative of ab-solute deficiency (TsAT <20% and ferritin < 100 ug/l), while in non-esA and non-dialy-

zed patients – at TsAT < 25% and ferritin < 200 µg/l, in dialyzed individuals at TsAT <25% and ferritin <300 µg/l [69]. both oral and intravenous routes of iron supplemen-tation are possible. The choice ought to be made for every patient individually depen-ding on initial iron concentration, response to current treatment, occurrence of unde-sirable effects of the therapy, possibility of saving vascular access and current blood loss. Also, patient’s comfort as well as the possibility of co-operation are vital. oral medications fail to provide full biological availability of iron, interact with other medi-cations and thus cause undesirable effects, mainly gastrointestinal ones, leading to difficulties in compliance with oral therapy [69,70]. In case of non-dialyzed patients, the choice of iron administration route com-monly depends on clinical status; oral route is most commonly selected for practical re-asons. Intravenous route is more effective in dialyzed individuals compared to oral one due to limited iron absorption. Higher effec-tiveness of intravenous administration than oral route has been shown by randomized studies aimed at the comparison of the two ways of treatment [71-74]. However, intra-venous therapy is related to serious unde-sirable effects, especially in non-dialyzed patients [75,76]. Frequent administration of intravenous preparations may increase the risk of developing heart diseases, promote bacterial infections and deteriorate diabe-tes and its complications [77]. However, it was not confirmed in the most recent study on oral vs iv iron treatment in non-dialyzed patients [78]. In FINd-CKd study the inci-dence of cardiac disorders and infections was similar between groups. At least one ferritin level ≥800 µg/L occurred in 26.6% of high ferritin ferric carboxymaltose patients, with no associated increase in adverse events. No patient with ferritin ≥800 µg/L discontinued the study drug due to adverse events. estimated glomerular filtration rate remained the stable in all groups [78].

According to erbp guidelines, both pe-ritoneal dialysis and non-dialysis patients can be first treated with oral medications [69]. Typically, 200 mg a day of elemental iron in three divisible doses is administe-red. If iron balance is not obtained within three months of therapy, intravenous ad-ministration ought to be implemented at doses of 20-60mg at every hemodialysis or 100-200mg at weekly intervals. Non--dialysis and peritoneal dialysis patients require every-week or every-month intra-venous iron doses. optimal IV iron dose is 25-150mg/week for first 6 months of esA therapy [69]. during first 3 months of esA therapy, dialyzed patients require the sup-plementation of approximately 1000 mg of iron. special caution ought to be kept when administering iron dextran to persons with diagnosed allergic reactions to other medi-cations. However, the individuals with over-sensitive response to this iron form show low risk of developing sensitivity to other intravenous iron preparations [79]. The most common undesirable effects of oral iron preparation are gastrointestinal symp-toms such as nausea, vomiting, abdominal

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pains, diarrhea and constipation [80]. The assessment of iron balance in patients with stable hemoglobin concentration not tre-ated with esA should be performed eve-ry 2-6 months. In the initial phase of esA therapy and intravenous iron treatment, the parameters of iron balance ought to be tested every 1-3 months and every 4-6 we-eks in case of oral therapy and next, after obtaining target hemoglobin value – every 1-2 months. Following the administration of oral iron dose, the iron parameters should be tested after at least a week from the last dose [28,69].

during the therapy, it is not recommen-ded to attempt to obtain TsAT>30% and ferritin > 500 µg/ml in both dialyzed and non-dialyzed patients. Intravenous iron tre-atment ought to be withdrawn in the indivi-duals with active systemic infection and in case ferritin concentration is over 800 µg/dl [69].

ESA treatmentThe decision on esA administration re-

quires prior identification and treatment of all possible and reversible causes of ane-mia including iron deficiency. Importantly, both benefits of esA (decreased number of blood transfusion, subsiding of clinical signs of anemia) and the risk of develo-ping adverse effects (arterial hypertension, myocardial infarction, stroke, thrombosis, heart failure) ought to be taken into consi-deration. patients with history of arterial hy-pertension, thromboembolic disease, past cerebral stroke, with active or past cancer are at a high risk of developing side effects. every decision on applying esA therapy ought to be made individually depending on the increase in anemia severity, respon-se to previous iron therapy, severity of clini-cal signs of anemia and possibility to avoid blood transfusion in the future. According to KdIGo guidelines, esA treatment sho-uld be started in patients before dialysis with hemoglobin concentration < 10 g/dl, while in dialyzed patients at Hb 9-10 g/dl. The dose ought to be established the way that minimal hemoglobin concentration is maintained at 9mg/dl. In case of patients reporting considerable improvement in the quality of life with higher hemoglobin con-centration, esA treatment implementation is justified at Hb >10 g/dl [28]. In non-dialy-zed individuals, the treatment implementa-tion at hemoglobin of approximately 10-12 g/dl compared to Hb 8-9.9 g/dl decreases the necessity to perform transfusion [81].

Initial dose of the medication depends of the severity of anemia, body mass and clinical picture. during the therapy, modifi-cations of the dose with respect to hemo-globin concentration, speed of changes in its concentrations and current clinical status are necessary. Monthly increase in hemoglobin ought to range between 1 and 2 g/dl and not exceed 2 g/dl. According to erbp, in case of no necessity to decrease Hb level, it is suggested not to withdraw esA treatment but only reduce the dose. If hemoglobin concentration increases to 11.5g/dl, the dose ought to be reduced by approximately 25%. If despite dose reduc-

tion, the increase in hemoglobin concentra-tion is still observed, the treatment may be withdrawn until hemoglobin starts decre-asing and then started again at a dose lo-wer than the previous one by 25%. during the therapy course, hemoglobin concen-tration should remain on the level of 10-12 g/dl. reaching hemoglobin concentration over 13g/dl should be avoided [28,69].

both subcutaneous and intravenous routes of esA administration are possi-ble depending on properties of particu-lar preparations, their tolerance, stage of advancement of chronic renal failure and patient’s clinical profile. The subcutaneous route is preferred in non-dialyzed patients and the individuals on peritoneal dialysis while intravenous route – in hemodialysis patients.

Hemoglobin concentration should be assessed at least once a month at the be-ginning of the therapy and next, every 3 months in non-dialyzed patients and every month in dialyzed ones.

lack of proper hemoglobin increase during the first month is considered as insufficient response to esA treatment. Therapy ineffectiveness may result from, among others, administration of too small doses of esA, insufficient iron supply, loss of blood, hyperthyroidism, infection, inef-fective dialysis, b12 and folic acid deficien-cy or malnutrition. rarely, erythropoietin aplasia caused by the occurrence of anti--erythropoietin antibodies may develop. According to observations, the number of erythropoietin aplasia cases was higher after subcutaneous administration compa-red to intravenous therapy [82].

It is not recommended to use andro-gens, vitamins and l-carnitine as a suppor-ting treatment in the course of esA therapy.

A vital element of anemia treatment in dialyzed patients is providing optimal dialysis as optimal conventional dialysis techniques provide visible benefits [83-86] and should be considered as the rationa-le of treating patients with anemia and the end-stage renal disease. This group of pa-tients shows a high risk of developing pro-tein-energetic deficiencies that may lead to anemia and thus regular monitoring of nutritional status is critical [87,88]. patients with low bMI more frequently show seve-re anemia [89,90]. obese CKd individuals with high bMI show higher hemoglobin concentration and need less esA (per 1kg of body mass) compared to non-obese in-dividuals [91,92].

red cell concentrate transfusion as a form of anemia treatment ought to be im-plemented only in special cases. The crite-ria of referring patients for transfusion are mainly clinical signs of anemia and not he-moglobin concentration itself. Transfusion is justified in case of patients requiring fast anemia treatment (hemorrhage, unstable coronary disease, scheduled surgical pro-cedure), lack of esA effectiveness and in patients with high risk of developing com-plications in esA therapy. According to erbp, in hemodynamically stable patients, transfusion may be considered at Hb <7 g/dl, or <8 g/dl in post-operative patients and

individuals with cardiovascular disease [69]. Transfusions ought to be avoided in case of renal transplant candidates. Treat-ment of anemia in post-transplant patients should be conducted as in non-dialyzed patients.

Summarydespite so high prevalence of anemia

in diabetes in the world, data on anemia in diabetic kidney disease are scarce. dia-betic patients often develop anemia while theirs serum creatinine is still within the normal range and anemia is more severe compared with the people with non-diabetic kidney disease. However, anemia in diabe-tes is relatively often unrecognized, in par-ticular, in outpatient settings. presence of anemia in diabetic kidney disease increase angiopathy and cardiovascular morbidity and mortality. regular screening for ane-mia might help to delay and reduce of oth-er complications associated with diabetes and the cardiovascular system. Treatment include mainly iron supplementation and erythropoietin stimulating agents.

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