ANEMIA &ANEMIA &ANEMIA & ANEMIA & HEMODIALYSISHEMODIALYSISHEMODIALYSISHEMODIALYSIS

The anemia of The anemia of CKDCKD is, in most patients, is, in most patients, normocytic and normochromic, and is normocytic and normochromic, and is y ,y ,due primarily to reduced production of due primarily to reduced production of erythropoietinerythropoietin by the kidney and to by the kidney and to y py p y yy yshortened red cell survival .shortened red cell survival .

Anemia in those with CKD should begin whenAnemia in those with CKD should begin whenAnemia in those with CKD should begin when Anemia in those with CKD should begin when the Hgb level is less than the Hgb level is less than 12 12 g/dL in females, g/dL in females, and Hgb levels of less thanand Hgb levels of less than 1313 55 g/dL in adultg/dL in adultand Hgb levels of less than and Hgb levels of less than 1313..55 g/dL in adult g/dL in adult males .males .Anemia becoming increasingly common asAnemia becoming increasingly common asAnemia becoming increasingly common as Anemia becoming increasingly common as GFRs decline below GFRs decline below 60 60 mL/min per mL/min per 11..73 73 mm2 2 ..

Anemia is associated with:Anemia is associated with:Independent risk factor for development of Independent risk factor for development of LVHLVHIndependent risk factor for hospitalization Independent risk factor for hospitalization (CV d(CV d CV l d)CV l d)(CV and non(CV and non--CV related)CV related)Increased CV morbidity and mortality Increased CV morbidity and mortality Poorer quality of lifePoorer quality of lifeHigher relative risk for death than diabetesHigher relative risk for death than diabetes

Anemia may be a risk factor forAnemia may be a risk factor forAnemia may be a risk factor for Anemia may be a risk factor for progression of chronic renal progression of chronic renal dysfunction todysfunction to ESRDESRD. .

OVERVIEW OF TREATMENTOVERVIEW OF TREATMENTOVERVIEW OF TREATMENT OVERVIEW OF TREATMENT OPTIONSOPTIONS

Red blood cell transfusionsRed blood cell transfusionsRed blood cell transfusionsRed blood cell transfusions

—— Among patients with CKD, red blood cell Among patients with CKD, red blood cell f i l i ll f l if i l i ll f l itransfusions are almost universally successful in transfusions are almost universally successful in

raising hemoglobin levels. raising hemoglobin levels.

Transfusions often can ameliorate the patient's Transfusions often can ameliorate the patient's symptoms and improve healthsymptoms and improve health--related quality of related quality of y p py p p q yq ylife. life. ComplicationsComplications includeinclude transfusiontransfusion--transmittedtransmittedComplicationsComplications include include transfusiontransfusion transmitted transmitted infection, immunologic sensitization, iron overload infection, immunologic sensitization, iron overload syndromes, volume overloadsyndromes, volume overload and/orand/or transfusiontransfusionsyndromes, volume overloadsyndromes, volume overload, and/or , and/or transfusion transfusion reactions. reactions.

AndrogensAndrogensAndrogensAndrogens

Prior to the availability of epoetin, androgens Prior to the availability of epoetin, androgens (which may increase endogenous(which may increase endogenous erythropoietinerythropoietin(which may increase endogenous (which may increase endogenous erythropoietinerythropoietinproduction, sensitivity of erythroid progenitors production, sensitivity of erythroid progenitors to the effects of erythropoietin and red bloodto the effects of erythropoietin and red bloodto the effects of erythropoietin, and red blood to the effects of erythropoietin, and red blood cell survival) were used regularly in the treatment cell survival) were used regularly in the treatment of anemia in dialysis patientsof anemia in dialysis patientsof anemia in dialysis patients. of anemia in dialysis patients.

Erythropoietin stimulating agentsErythropoietin stimulating agents::The administration of these agents is particularlyThe administration of these agents is particularlyThe administration of these agents is particularly The administration of these agents is particularly attractive because they practically eliminate the attractive because they practically eliminate the need for red cell transfusions with an attendantneed for red cell transfusions with an attendantneed for red cell transfusions, with an attendant need for red cell transfusions, with an attendant decrease in and/or risk for transfusiondecrease in and/or risk for transfusion--related related complications .complications .complications .complications .They also help They also help mobilize iron storesmobilize iron stores, which is , which is particularly beneficial in patients with CKD andparticularly beneficial in patients with CKD andparticularly beneficial in patients with CKD and particularly beneficial in patients with CKD and iron overload due to previous transfusions. iron overload due to previous transfusions.

EPO be given to predialysis patients with aEPO be given to predialysis patients with aEPO be given to predialysis patients with a EPO be given to predialysis patients with a hemoglobin concentration less than hemoglobin concentration less than 11 11 g/dL .g/dL .Target Hb levels in the range ofTarget Hb levels in the range of 1111 toto 1212 g/dLg/dLTarget Hb levels in the range of Target Hb levels in the range of 1111 to to 1212 g/dL g/dL among EPO treated predialysis patients with among EPO treated predialysis patients with CKDCKDCKD.CKD.We recommend NOT targeting Hgb levels We recommend NOT targeting Hgb levels bb 1313 /dL/dLabove above 13 13 g/dL. g/dL.

EPO is recommended for use in EPO is recommended for use in hemodialysis patients who have ahemodialysis patients who have ahemodialysis patients who have a hemodialysis patients who have a hemoglobin level of less than hemoglobin level of less than 11 11 g/dL.g/dL.b tt lit f lif ith tb tt lit f lif ith tbetter quality of life without an better quality of life without an increase in adverse reactions are increase in adverse reactions are

i t d ith H b l b ti t d ith H b l b t 1111associated with Hgb values between associated with Hgb values between 1111and and 12 12 g/dL compared to values below g/dL compared to values below thi l lthi l lthis level. this level.

EPO should NOT be started until iron statusEPO should NOT be started until iron statusEPO should NOT be started until iron status EPO should NOT be started until iron status has been evaluated.has been evaluated.Among patients with evidence of ironAmong patients with evidence of ironAmong patients with evidence of iron Among patients with evidence of iron deficiency, iron supplements should be given deficiency, iron supplements should be given first and iron deficiency corrected prior tofirst and iron deficiency corrected prior tofirst and iron deficiency corrected prior to first and iron deficiency corrected prior to initiating EPO. initiating EPO.

In addition other causes of anemia shouldIn addition other causes of anemia shouldIn addition, other causes of anemia should In addition, other causes of anemia should be excluded and hypertension should be be excluded and hypertension should be

d b f EPO h i bd b f EPO h i bcorrected before EPO therapy is begun. corrected before EPO therapy is begun.

To ensure effective erythropoiesis with ongoingTo ensure effective erythropoiesis with ongoingTo ensure effective erythropoiesis with ongoing To ensure effective erythropoiesis with ongoing EPO administration, adequate iron stores must EPO administration, adequate iron stores must be continually maintained in both CKD andbe continually maintained in both CKD andbe continually maintained in both CKD and be continually maintained in both CKD and dialysis patients. dialysis patients. Iron therapy be administered for maintenanceIron therapy be administered for maintenanceIron therapy be administered for maintenance Iron therapy be administered for maintenance therapy among most patients receiving EPO. therapy among most patients receiving EPO.

Oral iron is often effective in predialysis patientsOral iron is often effective in predialysis patientsOral iron is often effective in predialysis patients Oral iron is often effective in predialysis patients and those on peritoneal dialysis; by comparison, and those on peritoneal dialysis; by comparison, most hemodialysis patients require intravenousmost hemodialysis patients require intravenousmost hemodialysis patients require intravenous most hemodialysis patients require intravenous iron .iron .

DIAGNOSIS OF IRON DEFICIENCYDIAGNOSIS OF IRON DEFICIENCY ::DIAGNOSIS OF IRON DEFICIENCYDIAGNOSIS OF IRON DEFICIENCY ::The evaluation of patients with kidney disease The evaluation of patients with kidney disease and anemia must include redand anemia must include red blood cell indicesblood cell indicesand anemia must include red and anemia must include red blood cell indices, blood cell indices, reticulocyte count, serum ironreticulocyte count, serum iron, TIBC, percent , TIBC, percent transferrin saturation serum ferritin and testingtransferrin saturation serum ferritin and testingtransferrin saturation, serum ferritin, and testing transferrin saturation, serum ferritin, and testing for occult blood in stool. for occult blood in stool.

Absolute and functional iron deficiencyAbsolute and functional iron deficiencyAbsolute and functional iron deficiencyAbsolute and functional iron deficiency

Among hemodialysis patients, absolute iron Among hemodialysis patients, absolute iron deficiency is likely to be present when:deficiency is likely to be present when:deficiency is likely to be present when:deficiency is likely to be present when:The percent transferrin saturation (plasma iron The percent transferrin saturation (plasma iron di id d b TIBCdi id d b TIBC 100100) f ll b l) f ll b l 2020divided by TIBC x divided by TIBC x 100100) falls below ) falls below 2020 percent percent The serum ferritin concentration is less than The serum ferritin concentration is less than 200 200 ng/mL ng/mL

Functional deficiency is associated withFunctional deficiency is associated withFunctional deficiency is associated with Functional deficiency is associated with transferrin saturation ≤transferrin saturation ≤20 20 percent and elevated percent and elevated ferritin level (between approximatelyferritin level (between approximately 100100 toto 800800ferritin level (between approximately ferritin level (between approximately 100100 to to 800800ng/mL or even higher). ng/mL or even higher).

For maintenance iron therapy transferrinFor maintenance iron therapy transferrinFor maintenance iron therapy, transferrin For maintenance iron therapy, transferrin saturation be maintained below saturation be maintained below 50 50 percent and percent and the serum ferritin level belowthe serum ferritin level below 500500 ng/mLng/mLthe serum ferritin level below the serum ferritin level below 500500 ng/mL .ng/mL .Do not routinely administer intravenous iron to Do not routinely administer intravenous iron to patients with ferritin levels abovepatients with ferritin levels above 500500 ng/mLng/mLpatients with ferritin levels above patients with ferritin levels above 500500 ng/mL ng/mL and anemia, although each patient should be and anemia, although each patient should be individually assessedindividually assessedindividually assessed. individually assessed.

OVERVIEW OF DOSING REGIMENSOVERVIEW OF DOSING REGIMENS ::OVERVIEW OF DOSING REGIMENSOVERVIEW OF DOSING REGIMENS ::Among ironAmong iron--deficient hemodialysis patients, if deficient hemodialysis patients, if iron indices indicate absolute or functional ironiron indices indicate absolute or functional ironiron indices indicate absolute or functional iron iron indices indicate absolute or functional iron deficiency:deficiency:100100 ii b i hb i h100 100 mg mg iron sucroseiron sucrose can be given at each can be given at each consecutive hemodialysis treatment for a total of consecutive hemodialysis treatment for a total of 1010 d (d (10001000 i l)i l)10 10 doses (doses (10001000 mg in total). mg in total).

Repeat the initial loading regimen if theRepeat the initial loading regimen if theRepeat the initial loading regimen if the Repeat the initial loading regimen if the transferrin saturation remains below transferrin saturation remains below 20 20 percent, percent, the hemoglobin level does not increase to thethe hemoglobin level does not increase to thethe hemoglobin level does not increase to the the hemoglobin level does not increase to the target level, or the serum ferritin level remains target level, or the serum ferritin level remains belowbelow 200200 ng/mLng/mLbelow below 200 200 ng/mL. ng/mL.

Among predialysis and peritoneal dialysis ironAmong predialysis and peritoneal dialysis ironAmong predialysis and peritoneal dialysis, iron Among predialysis and peritoneal dialysis, iron is principally given is principally given orallyorally to treat and prevent to treat and prevent development of iron deficiencydevelopment of iron deficiencydevelopment of iron deficiency.development of iron deficiency.IV ironIV iron may be necessary and is typically given may be necessary and is typically given when iron indices fall below target levelswhen iron indices fall below target levelswhen iron indices fall below target levels, when iron indices fall below target levels, indicating the development of iron deficiency. indicating the development of iron deficiency.

Major adverse consequences with normal orMajor adverse consequences with normal orMajor adverse consequences with normal or Major adverse consequences with normal or nearnear--normal Hgb levels include normal Hgb levels include cerebrovascular eventscerebrovascular events arteriovenous accessarteriovenous accesscerebrovascular eventscerebrovascular events, , arteriovenous access arteriovenous access thrombosisthrombosis, and , and hypertensionhypertension..

Among hemodialysis patients, suggestAmong hemodialysis patients, suggestAmong hemodialysis patients, suggest Among hemodialysis patients, suggest administering EPO intravenously rather than administering EPO intravenously rather than subcutaneously. subcutaneously. yyIn general, to attain hemoglobin levels of In general, to attain hemoglobin levels of 11 11 g/dL or higher, a dose increase of g/dL or higher, a dose increase of 2525 percent percent g gg g ppwould be appropriate after four weeks if initial would be appropriate after four weeks if initial dosing levels do not result in a rate of increase in dosing levels do not result in a rate of increase in h h l bi f i lh h l bi f i l 00 33 00 55the hemoglobin of approximately the hemoglobin of approximately 00..33 to to 00..55

g/dL per week. g/dL per week.

Changing the dose of EPO more than once overChanging the dose of EPO more than once overChanging the dose of EPO more than once over Changing the dose of EPO more than once over a twoa two-- to fourto four--week period is unnecessary in week period is unnecessary in most instancesmost instancesmost instances. most instances. Among those with increases in hemoglobin of Among those with increases in hemoglobin of greater thangreater than 22 55 toto 33 g/dL per month the EPOg/dL per month the EPOgreater than greater than 22..55 to to 33 g/dL per month, the EPO g/dL per month, the EPO dose should be reduced by at least dose should be reduced by at least 25 25 percent. percent.

Hyporesponsiveness to EPOHyporesponsiveness to EPO ::Hyporesponsiveness to EPOHyporesponsiveness to EPO ::450 450 U/kg per week intravenous EPO or U/kg per week intravenous EPO or 300 300 U/kg per week subcutaneous EPO perU/kg per week subcutaneous EPO perU/kg per week subcutaneous EPO, per U/kg per week subcutaneous EPO, per K/DOQI .K/DOQI .Th f i EPOTh f i EPOThe most common cause of resistance to EPO The most common cause of resistance to EPO is absolute iron deficiency .is absolute iron deficiency .

Bone disease due to secondary Bone disease due to secondary h th idih th idihyperparathyroidism hyperparathyroidism Occult malignancy and unsuspected Occult malignancy and unsuspected hematologic disorders hematologic disorders MM /myelofibrosis/myelodysplasticMM /myelofibrosis/myelodysplasticMM /myelofibrosis/myelodysplastic MM /myelofibrosis/myelodysplastic syndrome. syndrome.

HemoglobinopathiesHemoglobinopathiesHemoglobinopathies Hemoglobinopathies The administration of ACE inhibitors and/or The administration of ACE inhibitors and/or ARBsARBsARBs. ARBs. Development of pure red cell aplasia associated Development of pure red cell aplasia associated

i h h f li i ii h h f li i iwith the presence of neutralizing antiwith the presence of neutralizing anti--erythropoietin antibodies erythropoietin antibodies Presence of HIV infection. Presence of HIV infection.

Chronic inflammation :presence of a failedChronic inflammation :presence of a failedChronic inflammation :presence of a failed Chronic inflammation :presence of a failed kidney transplant or an occult infection of an kidney transplant or an occult infection of an old nonfunctioning AV graft may underlie suchold nonfunctioning AV graft may underlie suchold nonfunctioning AV graft may underlie such old nonfunctioning AV graft may underlie such inflammation in some patients inflammation in some patients accumulation of aluminum in boneaccumulation of aluminum in boneaccumulation of aluminum in bone. accumulation of aluminum in bone.

Side effectsSide effectsTh id ff f EPOTh id ff f EPOThe most common side effects of EPO The most common side effects of EPO treatment, aside from hypertension and its treatment, aside from hypertension and its

l d bl h d h ( hi h il d bl h d h ( hi h irelated problems, are headache (which occurs in related problems, are headache (which occurs in 15 15 percent of cases) and an influenzapercent of cases) and an influenza--like like

d ( ff id ( ff i 55 ))syndrome (affecting syndrome (affecting 55 percent).percent).The influenzaThe influenza--like syndrome is of unknown like syndrome is of unknown etiology, but is responsive to antietiology, but is responsive to anti--inflammatory inflammatory drugs .drugs .

HTN following erythropoietin HTN following erythropoietin ::ApproximatelyApproximately 2020 toto 3030 percent of patients whopercent of patients whoApproximately Approximately 2020 to to 3030 percent of patients who percent of patients who receive receive erythropoietinerythropoietin iv may develop an iv may develop an elevation in diastolic pressure of elevation in diastolic pressure of 1010 mmHg or mmHg or pp ggmore . more . In comparison, the BP is less likely to rise after In comparison, the BP is less likely to rise after p yp ysubcutaneous administration . subcutaneous administration .

PREVENTION AND TREATMENTPREVENTION AND TREATMENT ::PREVENTION AND TREATMENTPREVENTION AND TREATMENT ::BP must be closely monitored in all patients BP must be closely monitored in all patients with CKD particularly during initiation withwith CKD particularly during initiation withwith CKD, particularly during initiation with with CKD, particularly during initiation with EPO. EPO. Th f EPOTh f EPO i d d h i b ii d d h i b iTherapy of EPOTherapy of EPO--induced hypertension begins induced hypertension begins with prevention.with prevention.The risk of hypertension can be ameliorated by The risk of hypertension can be ameliorated by raising the hematocrit slowly .raising the hematocrit slowly .

Antiplatelet agentsAntiplatelet agents may reduce the risk ofmay reduce the risk ofAntiplatelet agentsAntiplatelet agents may reduce the risk of may reduce the risk of EPOEPO--induced hypertension. induced hypertension. Why this might occur is not clear.Why this might occur is not clear.

Patients who still become hypertensive can bePatients who still become hypertensive can bePatients who still become hypertensive can be Patients who still become hypertensive can be treated with treated with fluid removalfluid removal (via dialysis and the (via dialysis and the administration of antihypertensive agentsadministration of antihypertensive agentsadministration of antihypertensive agentsadministration of antihypertensive agents. .

BetaBeta--adrenergic blockersadrenergic blockers and and vasodilatorsvasodilators should be considered asshould be considered asvasodilatorsvasodilators should be considered as should be considered as agents of first choice, although calcium agents of first choice, although calcium h l bl k d ACE i hibi lh l bl k d ACE i hibi lchannel blockers and ACE inhibitors also channel blockers and ACE inhibitors also

may be effectivemay be effective. .

The dose of EPO should be reduced orThe dose of EPO should be reduced orThe dose of EPO should be reduced or The dose of EPO should be reduced or discontinued for several weeks in severe discontinued for several weeks in severe

h h h ih h h icases or when other therapeutic measures cases or when other therapeutic measures are ineffective.are ineffective.

For hemodialysis patients in whom EPOFor hemodialysis patients in whom EPOFor hemodialysis patients in whom EPO For hemodialysis patients in whom EPO administration has been initiated or the dose has administration has been initiated or the dose has recently changed the hemoglobin should berecently changed the hemoglobin should berecently changed, the hemoglobin should be recently changed, the hemoglobin should be measured once per week to adequately assess the measured once per week to adequately assess the response; by comparison the hemoglobin ofresponse; by comparison the hemoglobin ofresponse; by comparison, the hemoglobin of response; by comparison, the hemoglobin of patients with stable hemoglobin levels and EPO patients with stable hemoglobin levels and EPO dose can be assessed every two to four weeksdose can be assessed every two to four weeksdose can be assessed every two to four weeks. dose can be assessed every two to four weeks.

Future Treatment Options for CKDFuture Treatment Options for CKD--Related AnemiaRelated Anemia

Continuous erythropoiesis receptor activatorContinuous erythropoiesis receptor activatorContinuous erythropoiesis receptor activator Continuous erythropoiesis receptor activator (CERA) (CERA) –– not FDA Approvednot FDA Approved

SC or IV dosing up toSC or IV dosing up to 44 week intervalweek intervalSC or IV dosing up to SC or IV dosing up to 44--week intervalweek intervalErythropoietinErythropoietin--mimetic peptidesmimetic peptides

l d i f i h ll f hll d i f i h ll f hllong duration of action that allows for once monthly long duration of action that allows for once monthly dosingdosing

H iH i I d ibl F S biliI d ibl F S biliHypoxiaHypoxia--Inducible Factor Stabilizer Inducible Factor Stabilizer first oral therapy for the treatment of anemia in first oral therapy for the treatment of anemia in CKDCKDCKD CKD