Anaemia management Indian Anaemia management Indian ScenaroScenaro

Presented by-Dr(Lt Col) Ashutosh Ojha, MDPDCDM StudentGMCH,Guwahati-32Moderator-Prof AK BarmanProf & HoD(Nephrology)

Estimates of prevalence of CKD in Estimates of prevalence of CKD in the USA: NHANES IIIthe USA: NHANES III

StageStage DescriptionDescriptionGFRGFR

(ml/min/1.73 (ml/min/1.73 mm22))

PrevalencePrevalence(%)(%)

11Kidney damage with Kidney damage with

normal or normal or GFR GFR9090 3.33.3

22Kidney damage withKidney damage with

mild mild GFR GFR 60–8960–89 3.03.0

33 Moderate Moderate GFR GFR 30–5930–59 44.3.3

44 Severe Severe GFR GFR 15–2915–29 0.20.2

55 Kidney failureKidney failure15 or15 or

(or d(or dialysisialysis))0.10.1

Coresh et al AJKD 2003

EXTENT OF CKD IN INDIAEXTENT OF CKD IN INDIA

India-diabetic capital. Every 5India-diabetic capital. Every 5thth Indian diabetic and Indian diabetic and

every 5every 5thth Indian Hypertensive Indian Hypertensive 40-50% of all chronic kidney disease is due to 40-50% of all chronic kidney disease is due to

diabetes diabetes

Prevalence of CKD Prevalence of CKD Chennai- 0.16Chennai- 0.16 Delhi- 0.78Delhi- 0.78

Incidence of CKD Incidence of CKD 151-232 per million population 151-232 per million population (Jha et al)(Jha et al) 785 per million population 785 per million population (Agarwal et al)(Agarwal et al)

Cause of End Stage Renal Disease Cause of End Stage Renal Disease (SJMCH)(SJMCH)

10%40%

28%

18%

4%

Diabetics

htn

IN

Others

Unknown

Challenges in Anaemia ManagementChallenges in Anaemia Management

Many patients affected by anaemiaMany patients affected by anaemia

0

5

10

15

20

25

30

35

40

45

50

> 90 60-89 30-59 15-29

Astor et al 2002n=15 625

Patients (%)

GFR (mL/min per 1.73 m2)

44

CKD REGISTRY INDIA

CORRECTION OF ANEMIACORRECTION OF ANEMIA

TARGET HAEMOGLOBIN =11-12 grams/dl

CKD AnaemiaCKD AnaemiaCorrelates with SurvivalCorrelates with Survival

Survival of CKD Patients by Haemoglobin Level

Reproduced courtesy of A Levin

CKD AnaemiaCorrelates With Survival

Time (months)

Pro

babi

lity

of S

urvi

val

0 3 6 9 12 15 18 21 24 27 30 33 36

0.70

0.75

0.80

0.85

0.90

0.95

1.00

Baselinehaemoglobin

Log-Rank Test: p = 0.0001

=

12 - 13 g/dL

11-12 g/dL

10-11 g/dL

10 g/dL

13 g/dL

<

Survival of CKD Patients by Haemoglobin Level

Reproduced courtesy of A Levin

Association between renal anaemia and Association between renal anaemia and relative risk of death or hospitalisationrelative risk of death or hospitalisation

Locatelli et al NDT 2004

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

<10 10–10.9 11–11.9 ≥120.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

<10 10–10.9 11–11.9 ≥12

Relative risk of death Relative risk of hospitalisation

RR, overall=0.95 per1 g/dl higher Hb (p=0.03)

RR, overall=0.96 per1 g/dl higher Hb (p=0.02)

1.22

1.02 10.91

1.29

1.091

1.07

p=0.06 p=0.86 Ref p=0.49 p<0.001 p=0.14 Ref p=0.44

(n) (1626) (952) (760) (682) (1521) (919) (733) (670)

RR

Hb (g/dl) at study entry

RR

Target of 10-12 g/dl is appropriateRenal Anemia correlates with outcome

CKD REGISTRY INDIA

Problems in anemia management in Problems in anemia management in CKDCKD

Common challenges faced are –Common challenges faced are –– Maintenance of stable hemoglobin levels in their Maintenance of stable hemoglobin levels in their

patientspatients– Avoid overshooting Hb targetsAvoid overshooting Hb targets– Balance intravenous iron & EPOBalance intravenous iron & EPO– Improve EPO response to use the lowest effective Improve EPO response to use the lowest effective

EPO doseEPO dose

A major concern is EPO hyporesponsiveness & A major concern is EPO hyporesponsiveness & insufficient iron replacementinsufficient iron replacementIV iron is important in managing these IV iron is important in managing these challenges to a large extentchallenges to a large extent

Kapoian T. Challenge of effectively using erythropoiesis-stimulating agents and intravenous iron. Am J Kidney Dis. 2008 Dec;52(6 Suppl):S21-8.

Challenges in Anaemia ManagementChallenges in Anaemia Management

Worldwide prevalence and incidence Worldwide prevalence and incidence of CKDof CKD

More than 1.7 million treated with renal More than 1.7 million treated with renal replacement therapy worldwide in 2004 replacement therapy worldwide in 2004 90% patients receiving RRT live in industrialized 90% patients receiving RRT live in industrialized countriescountriesThe incidence of CKD requiring renal replacement The incidence of CKD requiring renal replacement therapy has doubled over the last 15 yearstherapy has doubled over the last 15 yearsDramatically increasing prevalence predicted in the next Dramatically increasing prevalence predicted in the next 10 years largely due to the aging population and 10 years largely due to the aging population and increasing incidence of type 2 diabetesincreasing incidence of type 2 diabetes

El Nahas & Bello 2005Grassmann et al 2005

0

100

200

300

400

500

78 80 82 84 86 88 90 92 94 96 98 00 02

Challenges in Anaemia ManagementChallenges in Anaemia Management CKD incidence and prevalence CKD incidence and prevalence

increasingincreasing

Prevalent dialysis and transplant(2002: 431 284)

Prevalent dialysis (2002: 308 910)

Prevalent transplant (2002: 122 374)

Incident dialysis and transplant(2002: 100 359)

Year

No. of patients (thousands)

USRDS 2004 Annual Data Report

Challenges in Anaemia ManagementChallenges in Anaemia Management Undertreatment of anaemia remainsUndertreatment of anaemia remains

Locatelli et al 2004 Pisoni et al 2004

Mean Hb (g/dL)

6

7

8

9

10

11

12

13

Sweden

USA

Spain

Belgiu

m

Canad

a

Austra

lia /

NZ

Germ

any

Italy UK

France

Japan

Prevalent

Incident

Challenges in Anaemia ManagementChallenges in Anaemia Management Many patients below Hb targetMany patients below Hb target

Locatelli et al 2004 Pisoni et al 2004

(%) Patients with Hb <11 g/dL

0 10 20 30 40 50 60 70 80 90 100

Sweden

USA

Spain

Belgium

Canada

Australia / NZ

Germany

Italy

UK

France

Japan

PrevalentIncident

USR

DS Kaplan-Meier estimates of the probability of death or

a first non-fatal myocardial infarction in the normal-hematocrit groups

Mark A. Parazella,MD. CKD series: evaluation and treatment of anemia in chronic kidney disease. Hospital physician. 2003; 31-38,46

Mark A. Parazella,MD. CKD series: evaluation and treatment of anemia in chronic kidney disease. Hospital physician. 2003; 31-38,46

INDIAN BEST PRACTICE INDIAN BEST PRACTICE GUIDELINESGUIDELINES

Anaemia in CRF can be due to multiple Anaemia in CRF can be due to multiple causes, most commonly EPO deficiency causes, most commonly EPO deficiency and nutritional factors. Since EPO is and nutritional factors. Since EPO is expensive, all efforts must be made to expensive, all efforts must be made to correct nutritional deficiencies especially correct nutritional deficiencies especially iron deficiency and assessment of other iron deficiency and assessment of other nutritional factorsnutritional factors..

Indian Best Practices GuidelinesIndian Best Practices Guidelines

Guideline 1: Anaemia EvaluationGuideline 1: Anaemia Evaluation

(Evidence level A)(Evidence level A)

RBC indices / Peripheral smearRBC indices / Peripheral smear Iron / TIBC / Ferritin / Tranferrin Iron / TIBC / Ferritin / Tranferrin saturationsaturation Stool occult bloodStool occult blood Stool parasite testStool parasite test Serum B12 & Red cell folate Serum B12 & Red cell folate concentrationsconcentrations

Guideline 1 (a): Anaemia EvaluationGuideline 1 (a): Anaemia Evaluation

RBC indices / Peripheral smearRBC indices / Peripheral smear Iron / TIBC / Ferritin / Tranferrin Iron / TIBC / Ferritin / Tranferrin saturationsaturation Stool occult bloodStool occult blood Stool parasite testStool parasite test

A fuller work up should also include the A fuller work up should also include the following following

as indicated. as indicated. Serum B12 and red cell folate Serum B12 and red cell folate concentrationsconcentrations Differential white blood countDifferential white blood count Tests for haemolysis (haptoglobin, lactate Tests for haemolysis (haptoglobin, lactate

dehydrogenase)dehydrogenase)

Guideline 1 (a): Anaemia EvaluationGuideline 1 (a): Anaemia Evaluation

(contd..)(contd..) Serum and / or urine protein electrophoresis / Serum and / or urine protein electrophoresis / immunoblotting immunoblotting (where available). (where available). Serum aluminiumSerum aluminium Bone marrow examination in selected casesBone marrow examination in selected cases Assessment of occult gastrointestinal blood loss.Assessment of occult gastrointestinal blood loss.

Elements of this work up will be necessary if there is Elements of this work up will be necessary if there is clinical suspicion of primary haematological disorder clinical suspicion of primary haematological disorder (haemolysis, marrow dysplasia), macrocytosis, (haemolysis, marrow dysplasia), macrocytosis, aluminium poisoning or occult blood loss).aluminium poisoning or occult blood loss).

(Evidence level A)(Evidence level A)

Guideline 2(a): Diagnosis of Anaemia Guideline 2(a): Diagnosis of Anaemia of Chronic Renal Failureof Chronic Renal Failure

No cause other than CRF by above No cause other than CRF by above investigation.investigation.

GFR <30 in non-diabetics and 45ml/min. in GFR <30 in non-diabetics and 45ml/min. in diabetic patients (S. creat >2mg/dl). diabetic patients (S. creat >2mg/dl).

Measurement of plasma EPO concentration Measurement of plasma EPO concentration not not indicated. indicated.

Guideline 7: What are the causes Guideline 7: What are the causes of inadequate response to EPOof inadequate response to EPO (contd..)(contd..)

vi)vi) HemolysisHemolysis

VVii)ii) Osteitis fibrosaOsteitis fibrosa

viii)viii) Aluminium toxicityAluminium toxicity

ix)ix) Haemoglobinopathies (e.g. alpha & Beta Haemoglobinopathies (e.g. alpha & Beta thalassemias, sickle cell anaemia)thalassemias, sickle cell anaemia)

x)x) Multiple myeloma & other malignancies.Multiple myeloma & other malignancies.

xi)xi) Use of ACE-1 / ARB agentsUse of ACE-1 / ARB agents

Guideline 7(a): Resistance to EPO / Guideline 7(a): Resistance to EPO / inadequate response to EPOinadequate response to EPO

Failure to achieve target Hb concentrationFailure to achieve target Hb concentration

a) a) While receiving more than 300IU/kg/week S.C or While receiving more than 300IU/kg/week S.C or 450units IU/kg/week IV. 450units IU/kg/week IV.

b) Continued need for such dosage to maintain target b) Continued need for such dosage to maintain target in presence of adequate iron stores. in presence of adequate iron stores.

Resistance (hypo responsiveness) is relativeResistance (hypo responsiveness) is relative

In the absence of detectable abnormalities of any one In the absence of detectable abnormalities of any one of the above conditions – marrow examination is of the above conditions – marrow examination is indicated (for diagnosis of resistance) including indicated (for diagnosis of resistance) including haematologist reference.haematologist reference.

ROLE OF IRONROLE OF IRON

Need for IV iron in CKDNeed for IV iron in CKDIron deficiency in CKD patients develops primarily during Iron deficiency in CKD patients develops primarily during the correction of renal anemia by EPO treatmentthe correction of renal anemia by EPO treatmentAmong ESRD patients receiving EPO, Among ESRD patients receiving EPO, more than 50%more than 50% are iron deficient are iron deficient Approximately 150 mg of iron is necessary for an Approximately 150 mg of iron is necessary for an increase of 1 g/dl in hemoglobin levelincrease of 1 g/dl in hemoglobin levelCauses of anemia in CKD patients include –Causes of anemia in CKD patients include –– Inadequate intake of dietary ironInadequate intake of dietary iron– Blood loss during the extracorporeal procedure GI bleedingBlood loss during the extracorporeal procedure GI bleeding– Inadequate intestinal iron absorption and inhibition of iron release Inadequate intestinal iron absorption and inhibition of iron release

from macrophages from macrophages – Increased iron requirements during therapy with Increased iron requirements during therapy with erythropoiesis-erythropoiesis-

stimulating agents (ESAs).stimulating agents (ESAs).

1. Horl WH. Iron therapy for renal anemia: how much needed, how much harmful? Pediatr Nephrol 2007;22:480–9.

2. Guidelines for anemia of chronic kidney disease. NKF K/DOQI guidelines 2000. Available at: http://www.kidney.org/PROFESSIONALS/kdoqi/guidelines_updates/doqiupan_iii.html#5

IV iron in CKDIV iron in CKDIV iron therapy is superior to oral iron IV iron therapy is superior to oral iron supplementation in CKDsupplementation in CKD

Risk factors associated with IV iron therapy Risk factors associated with IV iron therapy acute allergic reactions acute allergic reactions long-term complications long-term complications caused by the caused by the generation of powerful generation of powerful oxidant species, oxidant species, Allergy is to related to dextran Allergy is to related to dextran moietymoiety

Iron dextran is associated with higher incidence Iron dextran is associated with higher incidence of Type I hypersensitivity than Iron sucroseof Type I hypersensitivity than Iron sucroseIron sucrose carries the lowest risk for Iron sucrose carries the lowest risk for hypersensitivityhypersensitivity

1. Horl WH. Iron therapy for renal anemia: how much needed, how much harmful? Pediatr Nephrol 2007;22:480–9.

Iron sucrose in kidney diseaseIron sucrose in kidney diseaseIron deficiency may be corrected by oral iron Iron deficiency may be corrected by oral iron supplementation but it is limited by –supplementation but it is limited by –– Poor compliancePoor compliance– Adverse gastrointestinal reactionsAdverse gastrointestinal reactions

IV iron preparations commonly used include IV iron preparations commonly used include iron sucrose, sodium ferric gluconate, & iron iron sucrose, sodium ferric gluconate, & iron dextrandextran

Iron sucrose is safer than iron dextran, is Iron sucrose is safer than iron dextran, is generally considered a safe and effective IV generally considered a safe and effective IV iron preparation in renal anemiairon preparation in renal anemia

1. Li H. Intravenous iron sucrose in peritoneal dialysis patients with renal anemia. Peritoneal Dialysis International 2008;28:149–54.

Iron sucrose in kidney diseaseIron sucrose in kidney diseaseIron sucrose is a novel and effective addition in Iron sucrose is a novel and effective addition in the management of ‘Anemia related to kidney the management of ‘Anemia related to kidney diseases’diseases’

Iron Sucrose is elemental iron which Iron Sucrose is elemental iron which replenishes body iron stores in patients with replenishes body iron stores in patients with iron deficiency iron deficiency

Approximately 25% of hemodialysis patients Approximately 25% of hemodialysis patients can be maintained on oral iron can be maintained on oral iron supplementation; the others require IV iron supplementation; the others require IV iron supplementationsupplementation

1. Dennis J. Cada. Iron Sucrose Injection. Drug Reviews From The Formulary, Volume 36, April 2001,404-4122. W.H. Horl, OPTA-therapy with iron and erythropoiesis-stimulating agents in chronic kidney disease, nephrology dial transplant. 2007 suppl 3;iii2-iii6

IndicationsIndications

IV iron sucrose is indicated in –IV iron sucrose is indicated in –– Non-Dialysis Dependent - Chronic Kidney Disease (NDD-Non-Dialysis Dependent - Chronic Kidney Disease (NDD-

CKD) patients receiving an erythropoietin CKD) patients receiving an erythropoietin – Non-Dialysis Dependent - Chronic Kidney Disease (NDD-Non-Dialysis Dependent - Chronic Kidney Disease (NDD-

CKD) patients not receiving an erythropoietin CKD) patients not receiving an erythropoietin – Hemodialysis Dependent - Chronic Kidney Disease (HDD-Hemodialysis Dependent - Chronic Kidney Disease (HDD-

CKD) patients receiving an erythropoietin CKD) patients receiving an erythropoietin – Peritoneal Dialysis Dependent - Chronic Kidney Disease Peritoneal Dialysis Dependent - Chronic Kidney Disease

(PDD-CKD) patients receiving an erythropoietin (PDD-CKD) patients receiving an erythropoietin

1. Venofer® [package insert]. Shirley, NY: American Regent, Inc.; 2007. 2. Hollands JM et al. Safety of High-Dose Iron Sucrose Infusion in Hospitalized Patients With Chronic Kidney Disease. Am J Health-Syst Pharm.  2006;63(8):731-734. 3. Mircescu G et al. Intravenous iron supplementation for the treatment of anaemia in pre-dialyzed chronic renal failure patients. Nephrol Dial Transplant 2006;21:120-4.

Iron sucrose in pre-dialysis CRF Iron sucrose in pre-dialysis CRF patientspatients

Patients undergoing chronic Patients undergoing chronic hemodialysis often present with anemiahemodialysis often present with anemiaIV iron therapy is administered in IV iron therapy is administered in conjunction with EPO as it helps prevent conjunction with EPO as it helps prevent EPO-hypo-responsivenessEPO-hypo-responsivenessStudy evaluated use of Iron sucrose in Study evaluated use of Iron sucrose in pre dialyzed patients of CRFpre dialyzed patients of CRF60 non-diabetic CRF patients were 60 non-diabetic CRF patients were included in the studyincluded in the study

Mircescu G ,et al. Intravenous iron supplementation for the treatment of anaemia in pre-dialyzed chronic renal failure patients. Nephrol Dial Transplant 2006;21:120-4.

ResultsResults60 patients included in the study60 patients included in the study58% of patients reporting a rise in Hb > 1 g/dL vs. baseline in the study58% of patients reporting a rise in Hb > 1 g/dL vs. baseline in the study80% of patients had a Hb > 10 g/dL vs. 44% at baseline80% of patients had a Hb > 10 g/dL vs. 44% at baseline55% had a Hb > 11 g/dL vs. 0% at baseline55% had a Hb > 11 g/dL vs. 0% at baselineMean serum iron concentration increased from –Mean serum iron concentration increased from –

– 73.9 73.9 µµg/dL at baselineg/dL at baseline– 84.2 84.2 µµg/dL at 6 monthsg/dL at 6 months– 101.8 101.8 µµg/dL at 12 months of therapyg/dL at 12 months of therapy

No worsening of renal function, and no adverse events were reported No worsening of renal function, and no adverse events were reported

Mircescu G et al. Intravenous iron supplementation for the treatment of anaemia in pre-dialyzed chronic renal failure patients. Nephrol Dial Transplant 2006;21:120-4.

Serum Iron concentration

Baseline 6 months 12 months0

102030405060708090

100110

Mean Serum Fe concentration

Time line

Mea

n s

eru

m F

e C

on

c.

Efficacy of Iron sucrose in Efficacy of Iron sucrose in hemodialysis patientshemodialysis patients

Schiesser et al conducted a prospective Schiesser et al conducted a prospective multicentre clinical trial in 50 iron-multicentre clinical trial in 50 iron-replete hemodialysis patients to replete hemodialysis patients to evaluate the efficacy of iron sucrose evaluate the efficacy of iron sucrose administration for 6 monthsadministration for 6 monthsHb level remained stable (12Hb level remained stable (12±±1.1 at 1.1 at baseline & 12.1baseline & 12.1±±1.5 g/dl at the end of 1.5 g/dl at the end of the study)the study)Reduced dose for EPOReduced dose for EPO

Schiesser et al. Weekly low-dose treatment with intravenous iron sucrose maintains iron status and decreases epoetin requirement in iron-replete haemodialysis patients. Nephrol Dial Transplant (2006) 21: 2841–5.

Iron sucrose IV reduces EPO Iron sucrose IV reduces EPO demand in dialysis patientsdemand in dialysis patients

In the study of Iron sucrose in In the study of Iron sucrose in hemodialysis patients conducted by hemodialysis patients conducted by Schiesser et al the dosage for the three Schiesser et al the dosage for the three different epoetins decreased by –different epoetins decreased by –– 38.5% with darbepoetin alfa38.5% with darbepoetin alfa– 6.3% with epoetin alfa6.3% with epoetin alfa– 8.3% with epoetin beta8.3% with epoetin beta

Schiesser et al. Weekly low-dose treatment with intravenous iron sucrose maintains iron status and decreases epoetin requirement in iron-replete haemodialysis patients. Nephrol Dial Transplant (2006) 21: 2841–5.

Results showing reduced EPO Results showing reduced EPO need with iron sucroseneed with iron sucrose

Schiesser et al showed reduced EPO Schiesser et al showed reduced EPO need with low dose maintenance iron need with low dose maintenance iron sucrose in their studysucrose in their study

Schiesser et al. Weekly low-dose treatment with intravenous iron sucrose maintains iron status and decreases epoetin requirement in iron-repletehaemodialysis patients. Nephrol Dial Transplant (2006) 21: 2841–5.

IV iron reduces EPO demand in IV iron reduces EPO demand in dialysis patientsdialysis patients

Chang et al studies the beneficial effects of 2 Chang et al studies the beneficial effects of 2 weekly IV iron supplementation compared to once weekly IV iron supplementation compared to once monthly IV iron in 149 iron replete patientsmonthly IV iron in 149 iron replete patientsEPO requirement EPO requirement reduced by 25%reduced by 25% when sereum when sereum ferritin & Transferrin saturation was maintained at ferritin & Transferrin saturation was maintained at high levels by administering 2 weekly IV iron high levels by administering 2 weekly IV iron compared to IV iron given once monthlycompared to IV iron given once monthlySignificant decrease in serum albumin, cholesterol Significant decrease in serum albumin, cholesterol & pre-dialysis creatinine when IV iron was & pre-dialysis creatinine when IV iron was administered 2 weekly for 1 yearadministered 2 weekly for 1 year

Chang CH et al. Reduction in erythropoietin doses by the use of chronic intravenous iron supplementation in iron-replete hemodialysis patients. Clin Nephrol. 2002;57:136-41.

IV iron reduces EPO demand in dialysis IV iron reduces EPO demand in dialysis patients – Results from Meta analysispatients – Results from Meta analysis

Compared to oral iron IV iron preparations significantly Compared to oral iron IV iron preparations significantly reduce the EPO requirement in dialysis patientsreduce the EPO requirement in dialysis patients

Rozen-Zvi et al. Intravenous Versus Oral Iron Supplementation for the Treatment of Anemia in CKD: Systematic Review and Meta-analysis. American Journal of Kidney Diseases 2008;52:897-906.

Iron sucrose in CKD patients not on Iron sucrose in CKD patients not on dialysisdialysis

Charytan et al compared oral iron with Charytan et al compared oral iron with Iron sucrose in 96 NDD-CKD patientsIron sucrose in 96 NDD-CKD patients

More IV iron patients (54.2%) attained More IV iron patients (54.2%) attained hemoglobin values > 11.0 g/dl hemoglobin values > 11.0 g/dl compared to oral iron patients (31.3%)compared to oral iron patients (31.3%)

There were no serious side effects with There were no serious side effects with iron sucroseiron sucrose

Charytan C et al. Comparison of intravenous iron sucrose to oral iron in the treatment of anemic patients with chronic kidney disease not on dialysis. Nephron Clin Pract. 2005;100(3):c55-62.

Efficacy & safety of Iron sucrose in Efficacy & safety of Iron sucrose in peritoneal dialysis patientsperitoneal dialysis patients

Li et al conducted a study to compare the clinical Li et al conducted a study to compare the clinical outcomes & safety of IV iron sucrose & oral ferrous outcomes & safety of IV iron sucrose & oral ferrous succinate in combination with rHuEPO therapy in succinate in combination with rHuEPO therapy in patients on maintenance PDpatients on maintenance PD46 patients were included – 26 received iron sucrose & 46 patients were included – 26 received iron sucrose & 20 oral 20 oral ironironHb & Hct increased significantly at 2 weeks in the IV Hb & Hct increased significantly at 2 weeks in the IV group compared with baselinegroup compared with baselineThe total response rate at 8 weeks was 94.8% for the IV The total response rate at 8 weeks was 94.8% for the IV group - significantly higher than that of the oral group group - significantly higher than that of the oral group (55.0%)(55.0%)There were no adverse events with IV ironThere were no adverse events with IV iron8 patients in the oral group had adverse GI effects8 patients in the oral group had adverse GI effects

Li H. Intravenous iron sucrose in peritoneal dialysis patients with renal anemia. Peritoneal Dialysis International 2008;28:149–54.

Results of Iron sucrose in PD Results of Iron sucrose in PD patients contd.patients contd.

Response rates to IV iron sucrose Response rates to IV iron sucrose therapy compared to Oral iron therapytherapy compared to Oral iron therapy

Li H. Intravenous iron sucrose in peritoneal dialysis patients with renal anemia. Peritoneal Dialysis International 2008;28:149–54.

Efficacy of Iron sucrose in ESRDEfficacy of Iron sucrose in ESRD

Iron sucrose in apparently iron-replete Iron sucrose in apparently iron-replete patients will decrease the EPO patients will decrease the EPO requirements for a given target requirements for a given target hematocrit in patients on maintenance hematocrit in patients on maintenance hemodialysis with end-stage renal hemodialysis with end-stage renal disease (ESRD)disease (ESRD)

1. Schiesser et al. Weekly low-dose treatment with intravenous iron sucrose maintains iron status and decreases epoetin requirement in iron-replete haemodialysis patients. Nephrol Dial Transplant (2006) 21: 2841–2845.

2. Shaldon S. The use of IV iron in the treatment of anaemia of ESRD patients on maintenance haemodialysis: an historical and personal view. Nephrol Dial Transplant (2007) 22: 23–25.

Safety of Iron sucroseSafety of Iron sucrose

Aronoff et al studied the safety of iron Aronoff et al studied the safety of iron sucrose in hemodialysis patientssucrose in hemodialysis patients

665 hemodialysis patients with 80 who 665 hemodialysis patients with 80 who had experienced previous intolerance to had experienced previous intolerance to other IV iron preparations were given iron other IV iron preparations were given iron sucrosesucrose

There were no serious or life-threatening There were no serious or life-threatening drug-related adverse eventsdrug-related adverse events

Aronoff GR et al. Iron sucrose in hemodialysis patients: Safety of replacement and maintenance regimens. Kidney International, 2004;66:1193–8.

Iron sucrose in patients Iron sucrose in patients hypersensitive to iron dextranhypersensitive to iron dextran

Iron dextran has been the only Iron dextran has been the only available parenteral iron available parenteral iron preparation for a long timepreparation for a long time

Its use has been associated with Its use has been associated with increased risk of allergic reactions, increased risk of allergic reactions, even after reaction-free previous even after reaction-free previous useuse

Haddad A et al. Use of Iron Sucrose in Dialysis Patients Sensitive to Iron Dextran. Saudi J Kidney Dis Transpl 2009;20(2):208-211

Safety of Iron sucrose compared Safety of Iron sucrose compared to other iron preparationsto other iron preparations

Rates of life-threatening ADEs –Rates of life-threatening ADEs –1.1. 0.6 per million for iron 0.6 per million for iron

sucrosesucrose

2.2. 0.9 per million for sodium 0.9 per million for sodium ferric gluconate complexferric gluconate complex

3.3. 3.3 per million for lower 3.3 per million for lower molecular weight iron dextranmolecular weight iron dextran

4.4. 11.3 per million per million for 11.3 per million per million for higher molecular weight iron higher molecular weight iron dextrandextran

Chertow GM et al. Update on adverse drug events associated with parenteral iron. Nephrol Dial Transplant (2006) 21: 378–382.

Safety of Iron preparations

1 2 3 40123456789

101112

Iron preparations

AD

E p

er m

illi

on

Dosing and administrationDosing and administration

NDD-CKD - ANDD-CKD - Administered as a total cumulative dministered as a total cumulative dose of 1,000 mg over a 14 days as a 200 mg dose of 1,000 mg over a 14 days as a 200 mg slow IV injection undiluted over 2 to 5 minutes slow IV injection undiluted over 2 to 5 minutes on 5 different occasions.on 5 different occasions.

HDD-CKD - AHDD-CKD - Administered undiluted as a 100 dministered undiluted as a 100 mg slow IV over 2 to 5 minutes or as an mg slow IV over 2 to 5 minutes or as an infusion of 100 mg, diluted in a maximum of 100 infusion of 100 mg, diluted in a maximum of 100 mL of NS over 15 minutes per consecutive mL of NS over 15 minutes per consecutive hemodialysis session for a total cumulative hemodialysis session for a total cumulative dose of 1,000 mg.dose of 1,000 mg.

1. Venofer® [package insert]. Shirley, NY: American Regent, Inc.; 2007.

Dosing and administration contd.Dosing and administration contd.

PDD-CKD - APDD-CKD - Administered undiluted as a total dministered undiluted as a total cumulative dose of 1,000 mg in 3 divided doses, cumulative dose of 1,000 mg in 3 divided doses, given by slow IV infusion, over 28 days:given by slow IV infusion, over 28 days:– 2 infusions of 300 mg over 1.5 hs 14 days apart2 infusions of 300 mg over 1.5 hs 14 days apart– Followed by 1 400 mg infusion over 2.5 h 14 days Followed by 1 400 mg infusion over 2.5 h 14 days

laterlater– Should be diluted in 250 mL of NSShould be diluted in 250 mL of NS

Low maintenance doses in hemodialysis Low maintenance doses in hemodialysis patients include 50mg injected into the venous patients include 50mg injected into the venous limb of the haemodialysis tubing system (slow limb of the haemodialysis tubing system (slow intravenous push at a rate of 10 mg/min)intravenous push at a rate of 10 mg/min)

1. Venofer® [package insert]. Shirley, NY: American Regent, Inc.; 2007.

Dosing and administration contd.Dosing and administration contd.

The usual dose is 100 mg administered one to The usual dose is 100 mg administered one to three times per week.three times per week.Most patients will require a minimum Most patients will require a minimum cumulative dose of 1000 mg of elemental iron cumulative dose of 1000 mg of elemental iron administered over 10 sequential dialysis administered over 10 sequential dialysis sessions to achieve a favorable responsesessions to achieve a favorable responsePatients may continue to receive IV iron Patients may continue to receive IV iron therapy at the lowest dose necessary to therapy at the lowest dose necessary to maintain target levels of hemoglobin, maintain target levels of hemoglobin, hematocrit & iron storage parametershematocrit & iron storage parameters

Cada DJ. Iron Sucrose Injection. Hospital Pharmacy 2001;36:404–12.

Monitoring parametersMonitoring parameters

Patients receiving regular IV iron therapy require Patients receiving regular IV iron therapy require monitoring of hematologic parameters & iron indices (Hb, monitoring of hematologic parameters & iron indices (Hb, Hct, TSAT, & ferritin) Hct, TSAT, & ferritin) Maintain TSAT between 20% and 50%Maintain TSAT between 20% and 50%Iron therapy should be withheld in patients with TSAT Iron therapy should be withheld in patients with TSAT ≥50% ≥50% Iron therapy should be withheld in patients with ferritin Iron therapy should be withheld in patients with ferritin values ≥800 ng/mL values ≥800 ng/mL Since transferrin saturation values increase rapidly after Since transferrin saturation values increase rapidly after IV administration of iron sucrose, serum iron values may IV administration of iron sucrose, serum iron values may be reliably obtained 48 hours after IV iron sucrose dosing be reliably obtained 48 hours after IV iron sucrose dosing

Cada DJ. Iron Sucrose Injection. Hospital Pharmacy 2001;36:404–12.

INDIAN BEST PRACTICE INDIAN BEST PRACTICE GUIDELINES … contdGUIDELINES … contd

Guideline 9: When to assess iron Guideline 9: When to assess iron status after EPO therapystatus after EPO therapy

1)1) Iron status must be assessed once in 3 Iron status must be assessed once in 3 months while on EPO therapy. months while on EPO therapy.

Guideline 9(a): When to assess Guideline 9(a): When to assess iron status after EPO therapy?iron status after EPO therapy?

CKD patients should have sufficient CKD patients should have sufficient

iron stores to maintain target Hb% iron stores to maintain target Hb% (Evidence).(Evidence).

To achieve this, sufficient iron to be To achieve this, sufficient iron to be administered.administered.

to maintain TSAT>20%to maintain TSAT>20%

Ferritin Ferritin >100ng/ml >100ng/ml

Guideline 9(a): When to assess iron Guideline 9(a): When to assess iron status after EPO therapy?status after EPO therapy?

(contd..)(contd..)

To achieve this level, aim at To achieve this level, aim at

- TSAT 30-40%- TSAT 30-40%

- Ferritin 200-500ng/ml - Ferritin 200-500ng/ml

(Evidence level B)(Evidence level B)

No benefit is achieved if TSAT >50% & serum No benefit is achieved if TSAT >50% & serum ferritin >800ng/ml and iron should not be ferritin >800ng/ml and iron should not be administered beyond this level (Evidence B)administered beyond this level (Evidence B)

Monitoring iron stores & Monitoring iron stores & supplement Ironsupplement Iron

1.1. During initiation of EPO & increased dose During initiation of EPO & increased dose of EPO.of EPO.

TSAT / serum ferritin to be checked every month TSAT / serum ferritin to be checked every month

in patients not receiving IV iron or once in three in patients not receiving IV iron or once in three

months in those receiving IV iron (opinion). months in those receiving IV iron (opinion).

2.2. Once target Hb% achieved, check iron stores Once target Hb% achieved, check iron stores

once in 3 months.once in 3 months.

Monitoring iron stores & Monitoring iron stores & supplement Ironsupplement Iron

(contd..)(contd..)

3.3. In doses of not more than 125mg IV Dextran, no In doses of not more than 125mg IV Dextran, no interruption of treatment to check iron stores (Evidence).interruption of treatment to check iron stores (Evidence).

4.4. However with large doses (1000mg IV Dextran), a gap of However with large doses (1000mg IV Dextran), a gap of

2 weeks after stopping IV iron, to be ensured to check 2 weeks after stopping IV iron, to be ensured to check

stores (Evidence).stores (Evidence).

5.5. CKD patients not treated with EPO with TSAT >20%, CKD patients not treated with EPO with TSAT >20%,

ferritin >100ng/ml, Iron stores to be checked once 3-6 ferritin >100ng/ml, Iron stores to be checked once 3-6

months (opinion).months (opinion).

Key pointsKey points

Anemia in CKD patients is commonAnemia in CKD patients is commonEPO therapy forms the mainstay of EPO therapy forms the mainstay of treatmenttreatmentEPO therapy alone may be ineffective EPO therapy alone may be ineffective unless supplemented by ironunless supplemented by ironOral iron supplementation has problems of Oral iron supplementation has problems of intoleranceintoleranceIV iron forms the best adjunct with EPO in IV iron forms the best adjunct with EPO in CKD patients.CKD patients.

Key pointsKey points

IV iron sucrose is one of the iron preparationsIV iron sucrose is one of the iron preparations

It is indicated in hemodialysis patients, non It is indicated in hemodialysis patients, non hemodialysis patients with or without EPO and hemodialysis patients with or without EPO and peritoneal dialysis patientsperitoneal dialysis patients

Efficacy is proved in each of these indicationsEfficacy is proved in each of these indications

Low maintenance dose of Iron sucrose keeps Low maintenance dose of Iron sucrose keeps Hb and Hct stable in hemodialysis patientsHb and Hct stable in hemodialysis patients

Key pointsKey points

Iron sucrose administration along with Iron sucrose administration along with EPO reduces the dose requirement of EPO reduces the dose requirement of EPOEPO

Iron sucrose can be safely given to Iron sucrose can be safely given to patients hypersensitive to iron dextranpatients hypersensitive to iron dextran

Iron sucrose is safer than other IV iron Iron sucrose is safer than other IV iron preparationspreparations

n = 56

n = 45

Laboratory and transfusion dataLaboratory and transfusion data

Parameter HD(n=157)

PD(n=126)

Pvalue

Hemoglobin (g/dl) 10.47 10.71 0.45

Serum ferritin (g/dl) 258.7 253.8 0.77

Transferrin saturation (%) 28.5 28.1 0.94

Mean number of transfusions (units) 4.59 2.17 0.01

% of patients receiving at least one transfusion 52.9% 40.9% 0.01

% of patients receiving transfusion if requiringbetween 6,000 and 10,000 units rHuEpo per week

59.5% 37.5% 0.02

House AA, et al, Nephrol Dial Transplant, 1998; 13:1763-1769

Patients receiving renal replacement therapy with HD Patients receiving renal replacement therapy with HD received more blood transfusions and more rHuEpo to received more blood transfusions and more rHuEpo to maintain the same hemoglobin as compared to those treated maintain the same hemoglobin as compared to those treated with PD.with PD.

Conclusion:Conclusion:

n = 56

n = 45

Patients on EPO

n = 56

170 ± 58

356 ± 9.6

050

100150200250300350400

HD PD

Serum ferritin (ng/dl)

n = 45

n = 56

Gokulnath et al, IJPD,16:22-28;2008

n = 56

n = 458.9 ± 1.6

10.8 ± 0.8

18 ± 6.0

26 ± 4.0

0 5 10 15 20 25 30

HD

PD

%

Hb(g/dl) % Saturation Ser. Alb(g/dl)

3 ± 0.24

3.5 ± 0.3

Patients on EPO

n = 56n = 56

n = 45

Gokulnath et al, IJPD,16:22-28;2008

n = 56

n = 45

Patients on EPO (IU/kg/wk)

n = 56

n = 45

n = 56

64 ± 21

116 ± 14

0

20

40

60

80

100

120

140

HD PD

n = 45

n = 56

Gokulnath et al, IJPD,16:22-28;2008

n = 56

n = 45

Patients on Serum Iron (mg)

n = 56

n = 45

n = 56

n = 45

n = 561210 ± 380

1860 ± 210

0

500

1000

1500

2000

HD PD

n = 45

n = 56

Gokulnath et al, IJPD,16:22-28;2008

n = 56

n = 45

5.6%

0.4%

0

1

2

3

4

5

6

HD PD Cohort followed up 30 months

Blood Transfusions in patients on Blood Transfusions in patients on Maintenance HD / CAPD Maintenance HD / CAPD

Gokulnath et al, IJPD,16:22-28;2008

STEM CELL THERAPYSTEM CELL THERAPY

FUTURE?FUTURE?

Thank youThank you