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Anemia where we stand

This document summarizes the current state of anemia treatment in chronic kidney disease (CKD) patients. It discusses the magnitude of the problem, clinical management including use of erythropoiesis-stimulating agents (ESAs), and future therapies. ESAs are currently the mainstay of treatment but have limitations like requiring high doses and increased risks at higher hemoglobin levels. Newer approaches being researched include stabilizing hypoxia-inducible factor to stimulate endogenous erythropoietin production, modulating the iron-regulating hormone hepcidin, and gene therapy to introduce the erythropoietin gene directly.

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Anemia Treatment In CKD patients: where we stand ? By Alaa Sabry., MD, FACP Mansoura University, Egypt
Focus Of The Presentation •Magnitude of the problem. •Clinical management. •Future therapy.
• A total of 12,077 adults participated in the National Health and Nutrition Examination Survey (NHANES) interview and examination components of the surveys in 2007–2008 and 2009–2010.
Consequences of Anemia
Anemia Management: USA (ESRD)
Anemia Management: USA
The pathogenesis of anemia of chronic kidney disease (CKD) Jodie L. Babitt, and Herbert Y. Lin JASN 2016.
Quality-of-life Sexual function Exercise capacity Endocrine function Immune function Angina Muscle metabolism LVH Hospitalizations Bleeding tendency Transfusions Brain / cognitive function Nutrition Depression Sleep patterns Anemia Control Benefits
• in 1835 Richard Bright: first suggestion was made that the kidney might be involved in erythropoiesis . • At the beginning of the twentieth century, Paul Carnot and Deflandre reported that serum from an anemic rabbit injected into a normal rabbit resulted in increased erythropoiesis. ( Hemopoitien) • Exactly 20 years later, Miyake et al isolated the hormone from urine of patients with aplastic anemia and named it EPO. History
Why CKD Patients need ESAs? (Erythropoiesis-Stimulating Agents)
Conversion Among ESA Conversion from Epoetin alfa to Darbepoetin alfa in patients with CKD not on dialysis: The dose conversion depicted in Table does not accurately estimate the once monthly dose of Darbepoetin alfa .
• CHr • CRP Primary Evaluation (Prior to ESAs Therapy) + other Investigations To address all correctable causes of anemia Fe Deficiency when: S. Ferritin  500 ng/ml S.TSAT  30% CHr: Detect iron stores in BM in last 1-2 days CRP: Exclude infection
ESAs Therapy Initiation Maintenance • When to initiate? • What is the dose? • How to follow initiation? • What is the target Hb level? • What is the dose & frequency? • How to follow maintenance?
Managing Iron Needs
Iron Markers in CKD Bahrainwala J. Semin Nephrol. 2016 Mar;36(2):94-8 The following thresholds are used to diagnose iron deficiency: ● Percent HRC >6 percent ● CHr <29 pg Am J Kidney Dis. 2016 Apr;67(4):548-58
Diagnosing iron deficiency Absolute deficiency • TSat • Flaws related to nutitional transferrin deficiency • Ferritin • Flaws related to inflammation • Percentage microcytic cells • Flaws related to cell swelling • Reticulocyte Hb content Functional deficiency • Pathophysiology • Inflammation, hepcidin, transferrin deficiency • Lab diagnosis • High ferritin, low TSAT • Clinical • Therapeutic testing
Iron repletion Oral • Poly-medication, side effects • Interactions • Poor response in dx patients • Absorption, target achievement Parenteral iron • Repletion • 1000mg divided in 5-10 sessions • May be repeated • Maintenance • 25-100 mg every 1-2 weeks • More frequent, every session 6-20 mg
Iron drug interactions • oral iron formulations interact with multiple drugs. • These interactions include reduced iron absorption • 1-Tetracycline antibiotics • 2- Proton pump inhibitors • 3- fluoroquinolones • 4-levothyroxine • 5- levodopa • Timing of administration of such drugs • Brookhart MA, et al. J Am Soc Nephrol. 2013; 24:1151-8.
Semin Nephrol. 2016 Mar;36(2):130-5
Semin Nephrol. 2016 Mar;36(2):130-5
Semin Nephrol. 2016 Mar;36(2):124-9
This mode of iron delivery provides smaller amounts of iron over hours compared with supplementation IV, which may help avoid oxidative toxicity Semin Nephrol. 2016 Mar;36(2):124-9
ESAs Initiation Caution (malignancy, stroke history) CKD ND  10 g/dl (no treatment) < 10 g/dl (according) CKD HD < 10 g/dl (treat) Transfusion!! Individualization (treat if > 10 g/dl) ESAs Initiation
Initiation Dose EPO α and  20-50 units/kg 3 times/week (I.V. dosage must be 20-30% higher than S.C. dosage) Darbepoetin alfa 0.45 g/kg once weekly or 0.75 g/kg once every two weeks (S.C. or IV) Methoxy polyethylene glycol- epoetin beta 0.6mcg (600ng)/kg every two weeks (S.C. or IV) ESAs Initiation Route of administration CKD ND SC CKD 5HD IV or SC
ESAs Initiation follow Up During the initiation phase of ESA therapy, measure Hb concentration at least monthly. (Not Graded)
ESAs Initiation Follow Up Serum Hb After 2 weeks of starting initiation If Hb increases >1 g/dL Decrease dose by ≥25% If Hb increases <1 g/dL Repeat serum Hb after another 2 weeks If Hb does not increase by >1 g/dL Increase dose by 25%
ESAs Therapy Maintenance • The target Hb level. • The dose & frequency. • Follow Up.
ESAs Maintenance Recommended target Hb level? ESAs Maintenance In general 11.5 Individualized >11.5 In all adults not >13 Higher risk of stroke, all cause, cardiovascular morbidity & mortality
CSN 11-12 g/dL EBPG >11 g/dL (upper limit not defined)DOQI 11-12 g/dL CARI 11-12 g/dL CVD 12-14 g/dL no CVD KDOQI 11-12 g/dL CARI >11 g/dL CVD 12-14 g/dL no CVD UK RA >10 g/dL EBPG >11 g/dL (upper limit individualised) CARI 11-12 g/dL CVD 12-14 g/dL no CVD CVD=cardiovascular disease EBPG=European Best Practice Guidelines CSN=Canadian Society Nephrology NICE=National Intitute of Health&Clinical excellance CARI=Caring for Australian with Renal Impairment Nephrol Dial Transplant (2009) 24: 348–354 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 KDOQI ≥11 g/dL (caution >13 g/dL) Anaemia Management Guidelines and Target Hb KDOQI 2007 update 11-12 g/dL (not intentionally >13 g/dL) UK NICE 10.5-12.5 g/dL 10-12 g/dL in children <2yr 2008 ERBP 2008 11-12 g/dL
ESAs Maintenance Are Higher levels better ? CKD -ND
Vs Placebo ` ESAs Maintenance Are Higher levels better ?
ESAs Maintenance follow UP Hb Follow up During ESAs Maintenance CKD ND At least every 3 months CKD 5D At least every month
Initiation Maintenance  No increase in Hb concentration from baseline.  After the first month of ESA.  After treatment with stable doses of ESA  Require 2 increases in ESA doses up to 50% beyond the dose at which they had been stable to maintain a stable Hb concentration. Initial Subsequent (Acquired)
• Epo Dose /Kg/week. ((300 IU/kg/week subcutaneously or 450 IU/kg/week intravenously). • EPO resistance index (ERI: rHuEPO/ kg/wk divided by hemoglobin level in g) . • It is assumed that, this method is more efficient to detect EPO resistance in HD patients.
ESAs Hyporesponsiveness Assessment & Investigations Treat the casue • CHr • CRP + other Investigations Fe ↓ Vit B12/folate ↓ Infection/Inflammation Blood loss • Occult blood in stool
ESAs Hyporesponsiveness Assessment & Investigations Treat the casue ↑ Blood loss dialysis line & filter Hyperparathyroidism Hemolysis (high LDH, unconjugated bilirubin) & other hemoglobinopathies Hypothyroidism Underdialysis Serum Alb & Nutrition ACE-I/ARB (for CKD ND) BM biopsy Pure Red Cell Aplasia (PRCA) Non-adherence Malignancy
ESAs Therapy Side Effects Influenza-like syndrome (affecting 5 %)* Unknown etiology** Respond to anti- inflammatory drugs** Hypertension *Bennett WM. J Am Soc Nephrol 1991; 1:990. ** Buur T etal. Clin Nephrol 1990; 34:230.
Hypertension • 15 % of cases.* • More common with I.V. route.** *Bennett WM. J Am Soc Nephrol 1991; 1:990. **Watson AJ etal. Am J Med 1990; 89:432. Therapy of EPO-induced hypertension begins with prevention. The risk of hypertension can be ameliorated by raising the hematocrit slowly. ESAs Therapy Side Effects
• Seizure • Increased blood clotting • Slight decrease of Kt/ V • Hyperkalemia • Pure Red cell aplasia (PRCA) ESAs Therapy Side Effects
Blood Transfusion
Clinical factors that trigger red blood cell transfusions in dialysis ordered by relative importance n=305 nephrologists; mean age=46 years; 21%women
Avoid, when possible, red cell transfusions to minimize the general risks related to their use. In patients eligible for organ transplantation, avoid, when possible, red cell transfusions to minimize the risk of allosensitization. Blood Transfusion
Benefits of red cell transfusions may outweigh the risks in patients in whom: 1. ESA therapy is ineffective (e.g., hemoglobinopathies, bone marrow failure, ESA resistance) 2. The risks of ESA therapy may outweigh its benefits (e.g., previous or current malignancy, previous stroke) 3. If rapid correction is required to stabilize the patient’s condition (e.g., acute hemorrhage, unstable coronary artery disease) 4. When rapid pre-operative Hb correction is required Blood Transfusion
ESA In Cancer Bohlius J, et al.Lancet 2009 53 trials (n = 13,933) Tonelli M, et al. Canadian Medical Association Journal 2009. 52 trials (n = 12,006)
What are the regulatory approved indications for ESAs?: • 1- Not indicated in patients receiving hormonal agents, therapeutic biologic products, or radio-therapy unless receiving concomitant myelosuppressive chemotherapy. • 2- In patients with a long life expectancy, the decision to administer ESAs should be based on a benefit-risk assessment with participation of the patient. (the type and stage of tumor, degree of anemia, life expectancy, treatment environment, and known risks of transfusions andESAs. • 3- Not be initiated at baseline hemoglobin levels ≥100 g/L. • 4-Should be used at the lowest dose needed to avoid transfusions . • 5- Hemoglobin levels should be maintained within the range of 100–120 g/L, and an increase in hemoglobin >10 g/L in a2-week period should be avoided. • 6- Following completion of chemotherapy ESAs should be discontinued.
• Current EPO analogue therapies rely upon supraphysiologic levels of recombinant variants of EPO to induce erythropoiesis . • Intravenous Or subcutaneous, Oral or nasal more convenient but the bioavailability is insufficient. • Unstable at Room temperatures , required cold chain from the manufacturing step till administration . • Inadequate handling increases the risk of immunization by the drug • Use of greater doses in CKD patients is associated with worsening hypertension and increased risk for CV events (myocardial infarction, hospitalization for congestive heart failure and stroke) . Szczech LA, al. Kidney Int 2008; 74: 791–798 Zhang Y, et al. Am J Kidney Dis 2004; 44: 866–876 Limitations
Future therapy
Future Erythropoiesis-Stimulating Agents
A- Erythropoietin Mimetic Peptides PEGINESATIDE
Peginesatide Phase 3 Clinical Trials
• Was approved by FDA in 2012. • Unfortunately, soon after launch, unexpected toxicity including anaphylaxis, which can be life-threatening, or fatal, was identified. • Approximately 0.02% of patients receiving the first dose of the drug intravenously died. • As a consequence Affymax, Inc. and Takeda Pharmaceutical Co. Ltd., along with the US FDA are informing the public of a voluntary recall of the entire lot of peginesatide injections in the user level . Locatelli F, Del Vecchio L. Expert Opin Pharmacother 2013 ;1277:8-14. Peginesatide
2- HIF STABILIZATION
Regulation of hypoxia inducible factor (HIF) activity. Abbreviations: EPO, erythropoietin; VHL, von Hippel Lindau protein.
Hb response Mean change from BL in serum hepcidin
• 1- Stimulating endogenous erythropoietin production without exogenous ESA therapy. • 2-These agents are orally active and thus there is potential for a noninjectable anemia therapy in the future. • 3-These molecules are able to modulate a number of other genes involved in erythropoiesis (eg, the erythropoietin receptor, transferrin, transferrin receptor, ferroportin, and divalent metal transporter in addition to the EPO gene). Haase VH. Am J Physiol Renal Physiol. 2010;299:F1-F13. Advantages of HIF stabilization therapy.
• The potential ability of these compounds to upregulate vascular endothelial growth factor (VEGF), which may have the adverse consequence of causing tumor growth and proliferative diabetic retinopathy . Toffoli S, Roegiers A, Feron O, et al. Angiogenesis. 2009;12:47-67 Possible disadvantages
3-Hepcidin Modulation
Overview of Hepcidin Antagonist 1 2 3 4
• A theoretical concern could be that inhibition of hepcidin might : • 1- Exacerbate the risk of infections, given its endogenous antimicrobial properties. • 1- Stabilization of HIF in some studies enhances tumor growth, stabilization of HIF in some studies enhances tumor growth • 3- Interruption of BMP (particularly BMP-6) may result in calcification of tissues (including peritoneum) . • A possible solution to this problem could entail the suppression of hepcidin to appropriate levels without complete inhibition of hepcidin production. Sun CC,. Am J Hematol 2012 Hepcidin Modulation
5- ERYTHROPOIETIN GENE THERAPY
• The basic methodology involved extracting a microbiopsy specimen of dermal cells, harvesting them, and transducing them with the EPO gene (using an adenovirus vector), and then reimplanting the preparation back into the mice. • TARGT (Transducer Autologous Regenerative Gene Therapy) system (formerly known as BioPump) was produced. ERYTHROPOIETIN GENE THERAPY
Harvesting, ex vivo culturing, implantation, and after implantation steps of the Biopump in patients. hEPO serum levels and reticulocyte counts in patients who received implants with the adenovector Biopump.
Conclusion
Kidney International (2014) 86, 676–678.
Despite new drugs, our ‘good old friend’ erythropoietin stimulating agents are our everyday life in nephrology practice.
Additional slides
Concerns with use of RBC transfusions? • 1-Increased risks of venous thrombotic events • 2-Arterial thrombotic events • 3-Mortality in hospitalized patients with cancer. • 4-- increased risks of infectious complications • 5-Acute respiratory distress syndrome • 3-Noninfectious adverse events include acute immunemediated reactions (such as antibody mediated hemolyticreactions, febrile non-hemolytic reactions, transfusion-related lung injury (TRALI), urticarial reactions, and anaphylaxis), and • 6- Nonimmune mediated transfusion reactions(hyperkalemia, hypocalcemia, hypothermia, and iron over-load) .
Epo Use in Cancer Patients • In Europe, ESAs are indicated for the treatment of symptomatic CIA in patients with a hemoglobin ≤100 g/L to increase hemoglobin to ≤120 g/L [30]. • They are not indicated for patients receiving (a) radiation therapy with a target hemoglobin of >140 g/L, (b) chemotherapy with a target hemoglobin of 120–140 g/L, or (c) neither chemo therapy nor radiation therapy with a target hemoglobin of 120 g/L. • In some clinical situations RBC transfusions should be the preferred treatment [30,32,33]. • The U.S. FDA approved labeling is more stringent than the Canadian labeling, in that it specifies that ESAs should not be used for patients undergoing chemotherapy with curative intent [34–36].
Health Canada approved indications for ESA therapy in patients with CIA. 2015
Refrigeration Room Temperature Shelf Life 0 5 7 31 0 5 10 15 20 25 30 35 Darbepoetin alfa Epoetin beta Epoetin alfa Days C.E.R.A.
• The Normal Hematocrit Study (NHS), a randomized, prospective, open-label trial, compared the attainment of hemoglobin concentration targets of 10 g/dL (low hemoglobin group) or 14 g/dL (normal hemoglobin group) in hemodialysis patients with coexisting heart failure or coronary artery disease. • The composite primary endpoint of all-cause mortality or first non fatal myocardial infarction was investigated. The study was stopped early due to safety concerns seen in the normal hemoglobin group. • Although the primary endpoint was not significant in this interim analysis (RR, 1.3; 95% CI, 0.9–1.9), a 7% increase in mortality rate in the normal hemoglobin group was observed.
ESAs Maintenance Recommended target Hb level CKD 5D • The only trial on CKD 5HD (N=110). • Two different targets (9.5-11 g/dl and >11 g/dl) vs placebo
CKD 5HD ESAs Maintenance Recommended target Hb level CKD 5D
Pure Red Cell Aplasia (PRCA) Polysorbate was used with Eprex instead of human serum albumin as a stabilizing agent Polysorbate stimulates the formation of EPO-Ab • ESA therapy for more than 8 weeks • Sudden rapid decrease in Hb concentration at the rate of 0.5 to 1.0 g/dl per week • OR requirement of transfusions at the rate of approximately 1 to 2 per week • Normal platelet and white cell counts, AND • Absolute reticulocyte count less than 10,000/l Treatment of PRCA • Stop ESA therapy • Peginesatide
Epo Preparations Darbepoietin Mircera
Measuring Hgb content of the reticulocytes
• The World Health Organization (WHO) defines anemia as a blood hemoglobin concentration of <13 g/dL in men and postmenopausal women and of <12 g/dL in women of childbearing age • KDIGO guidelines mirror the WHO definition of anemia for patients with CKD. • Serum Feritin: Main Iron storage protein <100 Absolute Iron deficiency. • Transferin sat: Glycoprotein secreted from the liver, main iron carrier to the cells. • Reticulocyte hemoglobin content (equivalent) • Under normal erythropoietic conditions, young erythrocytes (reticulocytes) are released from the bone marrow into circulation and become mature erythrocytes after several days. • Reticulocyte hemoglobin content (CHr),, quantifies hemoglobin mass in reticulocytes, providing information about a short-term change in iron status. • When measuring CHr (RetHe) in clinical practice, the time delay between blood sample draw and analysis should be taken into account when interpreting the results. Dialysis organizations in the United States typically use centralized laboratories with specimen shipment times ranging between 24 and 48 hours. Due to the quick maturation process of reticulocytes, there is a risk that this time delay may introduce measurement bias. • Percentage hypochromic red cells: • HRC are erythrocytes with mean cellular hemoglobin concentration (MCHC) less than 28 g/dL. • Soluble transferrin receptor • Iron uptake into erythroid precursors occurs through internalizing transferrin bound iron. The transferrin bound iron binds to transferrin receptors present on the surface of the plasma membrane and is internalized through endosomes ultimately leading to the release of iron. Plasma membrane bound transferrin receptors are released into the blood in form of a truncated sTfR. Ironrestricted erythropoiesis may cause overexpression of sTfR, as increased number of transferrin receptors may come off the surface of the erythroblasts and become detectable.53–55 • Hepcidin ?????
Oral iron supplements 200mg elemental iron / day
Semin Nephrol. 2016 Mar;36(2):130-5
Semin Nephrol. 2016 Mar;36(2):130-5
•Reticulocyte hemoglobin content (equivalent) • Under normal erythropoietic conditions, young erythrocytes (reticulocytes) are released from the bone marrow into circulation and become mature erythrocytes after several days. • Reticulocyte hemoglobin content (CHr),, quantifies hemoglobin mass in reticulocytes, providing information about a short-term change in iron status. •Percentage hypochromic red cells: • HRC are erythrocytes with mean cellular hemoglobin concentration (MCHC) less than 28 g/dL. •Soluble transferrin receptor • Iron uptake into erythroid precursors occurs through internalizing transferrin bound iron. The transferrin bound iron binds to transferrin receptors present on the surface of the plasma membrane and is internalized through endosomes ultimately leading to the release of iron. • Plasma membrane bound transferrin receptors are released into the blood in form of a truncated sTfR. Ironr estricted erythropoiesis may cause overexpression of sTfR, as increased number of transferrin receptors may come off the surface of the erythroblasts and become detectable. •Hepcidin ?????

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Anemia where we stand

  • 1.
    Anemia Treatment InCKD patients: where we stand ? By Alaa Sabry., MD, FACP Mansoura University, Egypt
  • 3.
    Focus Of ThePresentation •Magnitude of the problem. •Clinical management. •Future therapy.
  • 4.
    • A totalof 12,077 adults participated in the National Health and Nutrition Examination Survey (NHANES) interview and examination components of the surveys in 2007–2008 and 2009–2010.
  • 5.
  • 6.
  • 7.
  • 8.
    The pathogenesis ofanemia of chronic kidney disease (CKD) Jodie L. Babitt, and Herbert Y. Lin JASN 2016.
  • 9.
    Quality-of-life Sexual function Exercisecapacity Endocrine function Immune function Angina Muscle metabolism LVH Hospitalizations Bleeding tendency Transfusions Brain / cognitive function Nutrition Depression Sleep patterns Anemia Control Benefits
  • 10.
    • in 1835Richard Bright: first suggestion was made that the kidney might be involved in erythropoiesis . • At the beginning of the twentieth century, Paul Carnot and Deflandre reported that serum from an anemic rabbit injected into a normal rabbit resulted in increased erythropoiesis. ( Hemopoitien) • Exactly 20 years later, Miyake et al isolated the hormone from urine of patients with aplastic anemia and named it EPO. History
  • 11.
    Why CKD Patientsneed ESAs? (Erythropoiesis-Stimulating Agents)
  • 14.
    Conversion Among ESA Conversionfrom Epoetin alfa to Darbepoetin alfa in patients with CKD not on dialysis: The dose conversion depicted in Table does not accurately estimate the once monthly dose of Darbepoetin alfa .
  • 16.
    • CHr • CRP PrimaryEvaluation (Prior to ESAs Therapy) + other Investigations To address all correctable causes of anemia Fe Deficiency when: S. Ferritin  500 ng/ml S.TSAT  30% CHr: Detect iron stores in BM in last 1-2 days CRP: Exclude infection
  • 17.
    ESAs Therapy Initiation Maintenance •When to initiate? • What is the dose? • How to follow initiation? • What is the target Hb level? • What is the dose & frequency? • How to follow maintenance?
  • 18.
  • 21.
    Iron Markers inCKD Bahrainwala J. Semin Nephrol. 2016 Mar;36(2):94-8 The following thresholds are used to diagnose iron deficiency: ● Percent HRC >6 percent ● CHr <29 pg Am J Kidney Dis. 2016 Apr;67(4):548-58
  • 22.
    Diagnosing iron deficiency Absolutedeficiency • TSat • Flaws related to nutitional transferrin deficiency • Ferritin • Flaws related to inflammation • Percentage microcytic cells • Flaws related to cell swelling • Reticulocyte Hb content Functional deficiency • Pathophysiology • Inflammation, hepcidin, transferrin deficiency • Lab diagnosis • High ferritin, low TSAT • Clinical • Therapeutic testing
  • 23.
    Iron repletion Oral • Poly-medication,side effects • Interactions • Poor response in dx patients • Absorption, target achievement Parenteral iron • Repletion • 1000mg divided in 5-10 sessions • May be repeated • Maintenance • 25-100 mg every 1-2 weeks • More frequent, every session 6-20 mg
  • 25.
    Iron drug interactions •oral iron formulations interact with multiple drugs. • These interactions include reduced iron absorption • 1-Tetracycline antibiotics • 2- Proton pump inhibitors • 3- fluoroquinolones • 4-levothyroxine • 5- levodopa • Timing of administration of such drugs • Brookhart MA, et al. J Am Soc Nephrol. 2013; 24:1151-8.
  • 26.
    Semin Nephrol. 2016Mar;36(2):130-5
  • 27.
    Semin Nephrol. 2016Mar;36(2):130-5
  • 28.
    Semin Nephrol. 2016Mar;36(2):124-9
  • 29.
    This mode ofiron delivery provides smaller amounts of iron over hours compared with supplementation IV, which may help avoid oxidative toxicity Semin Nephrol. 2016 Mar;36(2):124-9
  • 30.
    ESAs Initiation Caution (malignancy, stroke history) CKDND  10 g/dl (no treatment) < 10 g/dl (according) CKD HD < 10 g/dl (treat) Transfusion!! Individualization (treat if > 10 g/dl) ESAs Initiation
  • 31.
    Initiation Dose EPO αand  20-50 units/kg 3 times/week (I.V. dosage must be 20-30% higher than S.C. dosage) Darbepoetin alfa 0.45 g/kg once weekly or 0.75 g/kg once every two weeks (S.C. or IV) Methoxy polyethylene glycol- epoetin beta 0.6mcg (600ng)/kg every two weeks (S.C. or IV) ESAs Initiation Route of administration CKD ND SC CKD 5HD IV or SC
  • 32.
    ESAs Initiation follow Up Duringthe initiation phase of ESA therapy, measure Hb concentration at least monthly. (Not Graded)
  • 33.
    ESAs Initiation Follow UpSerum Hb After 2 weeks of starting initiation If Hb increases >1 g/dL Decrease dose by ≥25% If Hb increases <1 g/dL Repeat serum Hb after another 2 weeks If Hb does not increase by >1 g/dL Increase dose by 25%
  • 34.
    ESAs Therapy Maintenance • Thetarget Hb level. • The dose & frequency. • Follow Up.
  • 35.
    ESAs Maintenance Recommended targetHb level? ESAs Maintenance In general 11.5 Individualized >11.5 In all adults not >13 Higher risk of stroke, all cause, cardiovascular morbidity & mortality
  • 36.
    CSN 11-12 g/dL EBPG >11 g/dL (upperlimit not defined)DOQI 11-12 g/dL CARI 11-12 g/dL CVD 12-14 g/dL no CVD KDOQI 11-12 g/dL CARI >11 g/dL CVD 12-14 g/dL no CVD UK RA >10 g/dL EBPG >11 g/dL (upper limit individualised) CARI 11-12 g/dL CVD 12-14 g/dL no CVD CVD=cardiovascular disease EBPG=European Best Practice Guidelines CSN=Canadian Society Nephrology NICE=National Intitute of Health&Clinical excellance CARI=Caring for Australian with Renal Impairment Nephrol Dial Transplant (2009) 24: 348–354 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 KDOQI ≥11 g/dL (caution >13 g/dL) Anaemia Management Guidelines and Target Hb KDOQI 2007 update 11-12 g/dL (not intentionally >13 g/dL) UK NICE 10.5-12.5 g/dL 10-12 g/dL in children <2yr 2008 ERBP 2008 11-12 g/dL
  • 37.
    ESAs Maintenance Are Higherlevels better ? CKD -ND
  • 38.
    Vs Placebo ` ESAs Maintenance AreHigher levels better ?
  • 40.
    ESAs Maintenance follow UP HbFollow up During ESAs Maintenance CKD ND At least every 3 months CKD 5D At least every month
  • 41.
    Initiation Maintenance  Noincrease in Hb concentration from baseline.  After the first month of ESA.  After treatment with stable doses of ESA  Require 2 increases in ESA doses up to 50% beyond the dose at which they had been stable to maintain a stable Hb concentration. Initial Subsequent (Acquired)
  • 42.
    • Epo Dose/Kg/week. ((300 IU/kg/week subcutaneously or 450 IU/kg/week intravenously). • EPO resistance index (ERI: rHuEPO/ kg/wk divided by hemoglobin level in g) . • It is assumed that, this method is more efficient to detect EPO resistance in HD patients.
  • 43.
    ESAs Hyporesponsiveness Assessment & Investigations Treat thecasue • CHr • CRP + other Investigations Fe ↓ Vit B12/folate ↓ Infection/Inflammation Blood loss • Occult blood in stool
  • 44.
    ESAs Hyporesponsiveness Assessment & Investigations Treat thecasue ↑ Blood loss dialysis line & filter Hyperparathyroidism Hemolysis (high LDH, unconjugated bilirubin) & other hemoglobinopathies Hypothyroidism Underdialysis Serum Alb & Nutrition ACE-I/ARB (for CKD ND) BM biopsy Pure Red Cell Aplasia (PRCA) Non-adherence Malignancy
  • 49.
    ESAs Therapy Side Effects Influenza-like syndrome (affecting5 %)* Unknown etiology** Respond to anti- inflammatory drugs** Hypertension *Bennett WM. J Am Soc Nephrol 1991; 1:990. ** Buur T etal. Clin Nephrol 1990; 34:230.
  • 50.
    Hypertension • 15 %of cases.* • More common with I.V. route.** *Bennett WM. J Am Soc Nephrol 1991; 1:990. **Watson AJ etal. Am J Med 1990; 89:432. Therapy of EPO-induced hypertension begins with prevention. The risk of hypertension can be ameliorated by raising the hematocrit slowly. ESAs Therapy Side Effects
  • 51.
    • Seizure • Increasedblood clotting • Slight decrease of Kt/ V • Hyperkalemia • Pure Red cell aplasia (PRCA) ESAs Therapy Side Effects
  • 53.
  • 54.
    Clinical factors thattrigger red blood cell transfusions in dialysis ordered by relative importance n=305 nephrologists; mean age=46 years; 21%women
  • 55.
    Avoid, when possible,red cell transfusions to minimize the general risks related to their use. In patients eligible for organ transplantation, avoid, when possible, red cell transfusions to minimize the risk of allosensitization. Blood Transfusion
  • 56.
    Benefits of redcell transfusions may outweigh the risks in patients in whom: 1. ESA therapy is ineffective (e.g., hemoglobinopathies, bone marrow failure, ESA resistance) 2. The risks of ESA therapy may outweigh its benefits (e.g., previous or current malignancy, previous stroke) 3. If rapid correction is required to stabilize the patient’s condition (e.g., acute hemorrhage, unstable coronary artery disease) 4. When rapid pre-operative Hb correction is required Blood Transfusion
  • 58.
    ESA In Cancer BohliusJ, et al.Lancet 2009 53 trials (n = 13,933) Tonelli M, et al. Canadian Medical Association Journal 2009. 52 trials (n = 12,006)
  • 59.
    What are theregulatory approved indications for ESAs?: • 1- Not indicated in patients receiving hormonal agents, therapeutic biologic products, or radio-therapy unless receiving concomitant myelosuppressive chemotherapy. • 2- In patients with a long life expectancy, the decision to administer ESAs should be based on a benefit-risk assessment with participation of the patient. (the type and stage of tumor, degree of anemia, life expectancy, treatment environment, and known risks of transfusions andESAs. • 3- Not be initiated at baseline hemoglobin levels ≥100 g/L. • 4-Should be used at the lowest dose needed to avoid transfusions . • 5- Hemoglobin levels should be maintained within the range of 100–120 g/L, and an increase in hemoglobin >10 g/L in a2-week period should be avoided. • 6- Following completion of chemotherapy ESAs should be discontinued.
  • 61.
    • Current EPOanalogue therapies rely upon supraphysiologic levels of recombinant variants of EPO to induce erythropoiesis . • Intravenous Or subcutaneous, Oral or nasal more convenient but the bioavailability is insufficient. • Unstable at Room temperatures , required cold chain from the manufacturing step till administration . • Inadequate handling increases the risk of immunization by the drug • Use of greater doses in CKD patients is associated with worsening hypertension and increased risk for CV events (myocardial infarction, hospitalization for congestive heart failure and stroke) . Szczech LA, al. Kidney Int 2008; 74: 791–798 Zhang Y, et al. Am J Kidney Dis 2004; 44: 866–876 Limitations
  • 62.
  • 63.
  • 64.
    A- Erythropoietin MimeticPeptides PEGINESATIDE
  • 65.
  • 66.
    • Was approvedby FDA in 2012. • Unfortunately, soon after launch, unexpected toxicity including anaphylaxis, which can be life-threatening, or fatal, was identified. • Approximately 0.02% of patients receiving the first dose of the drug intravenously died. • As a consequence Affymax, Inc. and Takeda Pharmaceutical Co. Ltd., along with the US FDA are informing the public of a voluntary recall of the entire lot of peginesatide injections in the user level . Locatelli F, Del Vecchio L. Expert Opin Pharmacother 2013 ;1277:8-14. Peginesatide
  • 67.
  • 68.
    Regulation of hypoxiainducible factor (HIF) activity. Abbreviations: EPO, erythropoietin; VHL, von Hippel Lindau protein.
  • 71.
    Hb response Mean changefrom BL in serum hepcidin
  • 75.
    • 1- Stimulatingendogenous erythropoietin production without exogenous ESA therapy. • 2-These agents are orally active and thus there is potential for a noninjectable anemia therapy in the future. • 3-These molecules are able to modulate a number of other genes involved in erythropoiesis (eg, the erythropoietin receptor, transferrin, transferrin receptor, ferroportin, and divalent metal transporter in addition to the EPO gene). Haase VH. Am J Physiol Renal Physiol. 2010;299:F1-F13. Advantages of HIF stabilization therapy.
  • 76.
    • The potentialability of these compounds to upregulate vascular endothelial growth factor (VEGF), which may have the adverse consequence of causing tumor growth and proliferative diabetic retinopathy . Toffoli S, Roegiers A, Feron O, et al. Angiogenesis. 2009;12:47-67 Possible disadvantages
  • 77.
  • 78.
  • 79.
    • A theoreticalconcern could be that inhibition of hepcidin might : • 1- Exacerbate the risk of infections, given its endogenous antimicrobial properties. • 1- Stabilization of HIF in some studies enhances tumor growth, stabilization of HIF in some studies enhances tumor growth • 3- Interruption of BMP (particularly BMP-6) may result in calcification of tissues (including peritoneum) . • A possible solution to this problem could entail the suppression of hepcidin to appropriate levels without complete inhibition of hepcidin production. Sun CC,. Am J Hematol 2012 Hepcidin Modulation
  • 80.
  • 81.
    • The basicmethodology involved extracting a microbiopsy specimen of dermal cells, harvesting them, and transducing them with the EPO gene (using an adenovirus vector), and then reimplanting the preparation back into the mice. • TARGT (Transducer Autologous Regenerative Gene Therapy) system (formerly known as BioPump) was produced. ERYTHROPOIETIN GENE THERAPY
  • 83.
    Harvesting, ex vivoculturing, implantation, and after implantation steps of the Biopump in patients. hEPO serum levels and reticulocyte counts in patients who received implants with the adenovector Biopump.
  • 84.
  • 85.
  • 87.
    Despite new drugs,our ‘good old friend’ erythropoietin stimulating agents are our everyday life in nephrology practice.
  • 88.
  • 93.
    Concerns with useof RBC transfusions? • 1-Increased risks of venous thrombotic events • 2-Arterial thrombotic events • 3-Mortality in hospitalized patients with cancer. • 4-- increased risks of infectious complications • 5-Acute respiratory distress syndrome • 3-Noninfectious adverse events include acute immunemediated reactions (such as antibody mediated hemolyticreactions, febrile non-hemolytic reactions, transfusion-related lung injury (TRALI), urticarial reactions, and anaphylaxis), and • 6- Nonimmune mediated transfusion reactions(hyperkalemia, hypocalcemia, hypothermia, and iron over-load) .
  • 94.
    Epo Use inCancer Patients • In Europe, ESAs are indicated for the treatment of symptomatic CIA in patients with a hemoglobin ≤100 g/L to increase hemoglobin to ≤120 g/L [30]. • They are not indicated for patients receiving (a) radiation therapy with a target hemoglobin of >140 g/L, (b) chemotherapy with a target hemoglobin of 120–140 g/L, or (c) neither chemo therapy nor radiation therapy with a target hemoglobin of 120 g/L. • In some clinical situations RBC transfusions should be the preferred treatment [30,32,33]. • The U.S. FDA approved labeling is more stringent than the Canadian labeling, in that it specifies that ESAs should not be used for patients undergoing chemotherapy with curative intent [34–36].
  • 95.
    Health Canada approvedindications for ESA therapy in patients with CIA. 2015
  • 96.
    Refrigeration Room Temperature ShelfLife 0 5 7 31 0 5 10 15 20 25 30 35 Darbepoetin alfa Epoetin beta Epoetin alfa Days C.E.R.A.
  • 97.
    • The NormalHematocrit Study (NHS), a randomized, prospective, open-label trial, compared the attainment of hemoglobin concentration targets of 10 g/dL (low hemoglobin group) or 14 g/dL (normal hemoglobin group) in hemodialysis patients with coexisting heart failure or coronary artery disease. • The composite primary endpoint of all-cause mortality or first non fatal myocardial infarction was investigated. The study was stopped early due to safety concerns seen in the normal hemoglobin group. • Although the primary endpoint was not significant in this interim analysis (RR, 1.3; 95% CI, 0.9–1.9), a 7% increase in mortality rate in the normal hemoglobin group was observed.
  • 98.
    ESAs Maintenance Recommended targetHb level CKD 5D • The only trial on CKD 5HD (N=110). • Two different targets (9.5-11 g/dl and >11 g/dl) vs placebo
  • 99.
  • 100.
    Pure Red CellAplasia (PRCA) Polysorbate was used with Eprex instead of human serum albumin as a stabilizing agent Polysorbate stimulates the formation of EPO-Ab • ESA therapy for more than 8 weeks • Sudden rapid decrease in Hb concentration at the rate of 0.5 to 1.0 g/dl per week • OR requirement of transfusions at the rate of approximately 1 to 2 per week • Normal platelet and white cell counts, AND • Absolute reticulocyte count less than 10,000/l Treatment of PRCA • Stop ESA therapy • Peginesatide
  • 101.
  • 102.
    Measuring Hgb contentof the reticulocytes
  • 105.
    • The WorldHealth Organization (WHO) defines anemia as a blood hemoglobin concentration of <13 g/dL in men and postmenopausal women and of <12 g/dL in women of childbearing age • KDIGO guidelines mirror the WHO definition of anemia for patients with CKD. • Serum Feritin: Main Iron storage protein <100 Absolute Iron deficiency. • Transferin sat: Glycoprotein secreted from the liver, main iron carrier to the cells. • Reticulocyte hemoglobin content (equivalent) • Under normal erythropoietic conditions, young erythrocytes (reticulocytes) are released from the bone marrow into circulation and become mature erythrocytes after several days. • Reticulocyte hemoglobin content (CHr),, quantifies hemoglobin mass in reticulocytes, providing information about a short-term change in iron status. • When measuring CHr (RetHe) in clinical practice, the time delay between blood sample draw and analysis should be taken into account when interpreting the results. Dialysis organizations in the United States typically use centralized laboratories with specimen shipment times ranging between 24 and 48 hours. Due to the quick maturation process of reticulocytes, there is a risk that this time delay may introduce measurement bias. • Percentage hypochromic red cells: • HRC are erythrocytes with mean cellular hemoglobin concentration (MCHC) less than 28 g/dL. • Soluble transferrin receptor • Iron uptake into erythroid precursors occurs through internalizing transferrin bound iron. The transferrin bound iron binds to transferrin receptors present on the surface of the plasma membrane and is internalized through endosomes ultimately leading to the release of iron. Plasma membrane bound transferrin receptors are released into the blood in form of a truncated sTfR. Ironrestricted erythropoiesis may cause overexpression of sTfR, as increased number of transferrin receptors may come off the surface of the erythroblasts and become detectable.53–55 • Hepcidin ?????
  • 106.
    Oral iron supplements 200mgelemental iron / day
  • 107.
    Semin Nephrol. 2016Mar;36(2):130-5
  • 108.
    Semin Nephrol. 2016Mar;36(2):130-5
  • 109.
    •Reticulocyte hemoglobin content(equivalent) • Under normal erythropoietic conditions, young erythrocytes (reticulocytes) are released from the bone marrow into circulation and become mature erythrocytes after several days. • Reticulocyte hemoglobin content (CHr),, quantifies hemoglobin mass in reticulocytes, providing information about a short-term change in iron status. •Percentage hypochromic red cells: • HRC are erythrocytes with mean cellular hemoglobin concentration (MCHC) less than 28 g/dL. •Soluble transferrin receptor • Iron uptake into erythroid precursors occurs through internalizing transferrin bound iron. The transferrin bound iron binds to transferrin receptors present on the surface of the plasma membrane and is internalized through endosomes ultimately leading to the release of iron. • Plasma membrane bound transferrin receptors are released into the blood in form of a truncated sTfR. Ironr estricted erythropoiesis may cause overexpression of sTfR, as increased number of transferrin receptors may come off the surface of the erythroblasts and become detectable. •Hepcidin ?????