Anemia is a common complication of chronic kidney disease that can cause fatigue. While the kidneys normally produce erythropoietin to stimulate red blood cell production, CKD patients have relative erythropoietin deficiency. This leads to anemia which, if left untreated, can negatively impact quality of life and cardiovascular health. Erythropoiesis-stimulating agents and iron supplementation are used to treat anemia in CKD, though the appropriate hemoglobin target level remains an area of ongoing research and debate given risks identified with higher targets in some studies.

1. DM SeminarANEMIA IN CHRONIC KIDNEY DISEASE Dr. Vishal Golay 22/07/2011

2. “Once my doctor began treating my kidney disease, my greatest challenge was the constant exhaustion. Fortunately, my doctor explained that anemia was causing my exhaustion and that people with serious illnesses, like kidney disease, may be at increased risk for anemia. ” Alonzo Mourning

3. Historical background Richard Bright (1836): first observed that anemia was a complication of renal failure. Robert Christison: further described renal anemia. Miyake (1977): purified and identified erythropoietin. Eschbach (Dec 2, 1985): first human use of EPO

4. Seminar overview Burden of anemia in CKD. Effects of Anemia in patients with CKD. Normal Erythropoiesis and Causes of anemia in CKD. ESA and Iron therapy. Evaluation of patients. Treatment. Controversies

5. Definition Anemia is a condition in which the number of RBCs or their oxygen-carrying capacity is insufficient to meet physiologic needs, which vary by age, sex, altitude, smoking, and pregnancy status (WHO). For diagnosis and further evaluation Hb values according to NKF guidelines:• <13.5 g/dL in adult males. (WHO-13g/dL)• <12.0 g/dL in adult females.

7. Burden of anemia in CKD According to the NHANES III data, the drop in Hb was significant in males whose GFR dropped below 75ml/min and females whose GFR dropped below 45ml/min

8. Burden of anemia in CKD 68 51.5 -5

9. Burden of anemia in CKD Curr Med Res Opin 20:1501-1510, 2004

10. Caution in interpreting results of trials Many studies that examined the relationship between Hb level and kidney function: Have been cross-sectional and not longitudinal in design. Described patients entered into clinical trials or seen by nephrologists, which are not a truly representative sample of patients with CKD. Included small numbers of patients with lower levels of kidney function. Used a great variety of methods to assess level of kidney function. It therefore is difficult to determine whether the variability in Hb at levels of kidney function is caused by variability in measurements of kidney function or variability associated with CKD itself. Used the MDRD4 formula to estimate GFR, the precision of which decreases at higher levels of kidney function. Did not describe the cause of the anemia in patients with CKD. KDOQI 2006

11. Effects of anemia (QOL) QUALITY OF LIFE: Anemia results in poorer quality of life in patients with renal failure. This correlation can be proven by the poor quality of life scores in patients with lower Hb values. Many observational as well as RCT have positively demonstrated that the QOL scores improved in patients who were given ESA and iron to increase their Hb

12. Effects of anemia(mortality) Generation of hypoxia due to anemia is poorly tolerated in patients with preexisting cardiac and vascular diseases. Compensatory mechanisms leads to development of LVH. Observational studies do show an increase in mortality in patients with CKD but not direct casualty. Interventional studies (DOPPS) show that for an increase of 1g/dL of Hb results in 4% decline in mortality. Also, Medicare data show that CKD=100% and CKD+Anemia=270% in 2-yr mortality risk.

13. EFFECTS of anemia on CV health CV disease related mortality is 15 times more in patients with CKD. 50% of deaths in patients with CKD are due to CV disease. LVH is the most common abnormality seen in patients with CKD and there is a strong correlation between anemia and LVH. Tissue hypoxia due to anemia is the principal stimuli triggering the compensatory changes that stresses the CV system

14. Other effects of anemia in ckd Acceleration of progression of kidney disease by oxygen deprivation. Increased risk of bacteremia (11% increased risk for every 1g/dl fall in Hb) Detrimental effects on brain and cognitive functions.

15. Normal erythropoiesis Degradation Hypoxia HIF-1a HRE EPO PHD of ODD Adequate O2 VHL

16. Normal erythropoiesis

17. Causes of anemia in CKD Relative EPO deficiency. Shortened RBC survival Bone marrow suppression. Other substrate deficiencies(B12 and folic acid) Iron deficiency. Blood loss

19. Erythropoietin “hemopoietine” 30.4 kDa glycoprotein hormone, plays a central role as a growth factor that sustains the survival of erythroid progenitor cells. Primary site of production is the liver in the fetus and kidneys after birth. Major sites of production-peritubular capillary endothelial cells and peritubular fibroblasts.

20. Erythropoietin Normal levels-10-30U/L 1 unit of EPO=erythropoietic effect in animals as occurs after stimulation with 5µmol of cobalt chloride. The EPO-receptor is a transmembrane receptor that belongs to the cytokine receptor superfamily. Receptor undergoes homodimerization after binding to EPO triggering downstream pathways(Ras/MAPk, JNK/MAPk, JAK/STAT and PI3. This activation promotes increased survival of precursor cells.

21. CKD and EPO EPO levels may be same or higher in patients with CKD than in normal nonanemic persons. Concept of relative EPO deficiency. Relationship between EPO and Hb depends on the severity of renal failure. The measurement of EPO levels in CKD is not helpful for making the diagnosis of anemia.

22. Evaluation Diagnosis of anemia should be made and further evaluation should be initiated once Hb is <13.5g/dL for males and <12g/dL for females. This definition represents the mean Hb of the lowest fifth percentile of the sex-specific general adult population This is different from the WHO definition (due to the different patient data used for making the recommendations)

23. Evaluation Preliminary investigations: CBC with PBS (sampling in HD-CKD patients should be timed to midweek predialysis) Red cell indices Further evaluation of cause of anemia should be based on the findings of CBC. Reticulocyte count and its corrections (index and RPI) Serum Iron Profile. Causes of anemia other than EPO deficiency should be considered when the severity of anemia is disproportionate to the impairment of renal function, there is evidence of iron deficiency, or there is evidence of leukopenia or thrombocytopenia.

24. KDOQI 2006 Anemia Guidelines

25. Iron Profile in CKD KDOQI recommends using ferritin and TSAT or CHr The evaluation of the cause of anemia should always precede initiation of ESA. Iron status evaluation serves two purposes: To assess the potential of contribution of iron deficiency To direct further evaluation for GI blood losses Use of iron indices for following up therapy is not very clear.

27. Iron Profile in CKD In ND-CKD, ferritin levels less than 25 ng/mL in males and less than 12 ng/mL in females suggest that storage-iron depletion is contributing to anemia. However in HD-CKD, ferritin is less reliable Iron-deficiency erythropoiesis is most likely to contribute to anemia when TSAT results are less than 16%. However, the clinical utility of TSAT is impaired by the absence of a diagnostic threshold.

28. Benefits of anemia treatment in ckd

29. ESA in treatment of renal anemia rHuEPO was genetically modified proteins that were very similar to the nascent EPO. Contained the 165AA backbone with one O-linked and three N-linked gycosylated chains. There gycosailylated chains contain variable amounts of sialic acid residues. Many forms of rHuEPO are available: Alfa, beta(NeoRecormon, Roche), omega, delta(Dynepo), pegylated forms

30. Pegylated ESA Methoxy polyethylene glycol-epoetin beta is made from erythropoietin by chemically linking the N-terminal amino group or the Є-amino group of any lysine present in the protein with methoxy polyethylene glycol butanoic acid. The average molecular weight is approximately 60kDa Marketed as Mircera(Roche)

31. Darbepoietinalfa(NESP)

33. Newer ESA’s Hematide: Novel peptide ESA which is not structurally related to EPO but mimics the propertied of EPO. currently in phase III of its clinical development program. Properties unique to hematide are: greater ex vivo stability,a prolonged pharmacodynamic action, a different immunogenicity profile with no cross-reactivity between Hematideand anti-EPO antibodies, and a simple manufacturing process involving synthetic peptide chemistry. HIF stabilizers GATA inhibitors

34. Iron therpy Oral formulations (sulfate, gluconate, fumarate, polysaccharide complex) Parenteral (iv) formulations (dextran, gluconate, sucrose, ferric carboxy maltose). In patients with HD-CKD iv formulations are the only form to be used (KDOQI) Newer formulations are associated with significantly fewer side effects. The exact schedule for delivery needs to be optimized for each patient and there should be regular monitoring of Fe stores. Iv iron therapy should be guided by the iron status of the patient rather than empirical Rx. Approx 1000mg of Fe over 2-3 weeks is necessary to overcome the deficiency

35. Comprehensive therapy

36. Monitoring therapy

37. Monitoring therapy Hb levels should be monitored at least once a month during ESA therapy (KDOQI-2006) Target rise of Hb should be in the range of 1-2g/month. Iron profile should be done at least once a month during the initial period of therapy and then one every 3 months during the maintenance phase

38. Failure of esa therapy

39. Hemoglobin target-evolving concepts Normal HematocritCardiac Trial (1998): suggested that attempts to normalize hematocrit in hemodialysis patients was associated with harm. KDOQI(1991): Hb targets of 11-12g/dl Many observational studies were published after that which showed better outcomes with higher Hb targets and so this upper limit was liberalized

40. Hemoglobin target-evolving concepts KDOQI 2006 Anemia Guidelines

41. Hemoglobin target-evolving concepts Two large RCT’s CHOIR and CREATE were published in November 2006 showing no benefit in one (CREATE) and harm in the other (CHOIR) with respect to cardiovascular outcomes in subjects randomized to a higher target hemoglobin level. The high burden of cases and the cost involved in maintain higher Hb levels was the main trigger for continuous debate on the adequate upper limit o

42. TREAT trial(nejm, nov 2009) randomized, double-blind, placebo-controlled trial conducted at 623 sites in 24 countries. 4038 patients with diabetes, chronic kidney disease, and anemia, we randomly assigned 2012 patients to darbepoetinalfa to achieve a hemoglobin level of approximately 13 g per deciliter 2026 patients to placebo, with rescue darbepoetinalfa when the hemoglobin level was less than 9.0 g per deciliter. The primary end points were the composite outcomes of death or a cardiovascular event (nonfatal myocardial infarction, congestive heart failure, stroke, or hospitalization for myocardial ischemia) and of death or end-stage renal disease.

43. TREAT trial The use of darbepoetinalfa (to achieve a higher Hb target) in patients with diabetes, chronic kidney disease, and moderate anemia who were not undergoing dialysis did not reduce the risk of either of the two primary composite outcomes (either death or a cardiovascular event or death or a renal event) and was associated with an increased risk of stroke. This risk may outweigh the potential benefits.

44. Kdigo position statement The current evidence, based on mortality data, for hemoglobin target levels intentionally aimed with ESA treatment in CKD patients treated indicates that levels of >13 g per 100 ml can be associated with harm, levels of 9.5–11.5 g per 100 ml are associated with better outcomes compared with >13 g per 100 ml for levels between 11.5 and 13 g per 100 ml, there is no evidence at this time for harm or benefit compared with higher or lower levels. Locatelli et al, Kidney Int; July 2008

45. Take home message Anemia is a significant contributor to mortality and morbidity in CKD. ESA and iron supplementation forms the core of anemia management and has to be understood in detail. The data on the upper limit of target Hb is conflicting but there is a trend towards a lower value.

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