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E rythropoietin -stimulating agents resistance and new anemia therapies. Narrative Review. Fellow 潘恆之 /VS 鄭昌錡. Outline. Introduction. EPO resistance. New anemia therapies. Introduction. Definition of anemia in CKD : Hgb <13.5 g/dl for male ; Hgb <12.0 g/dl for female

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e rythropoietin stimulating agents resistance and new anemia therapies

Erythropoietin-stimulating agents resistance and new anemia therapies

Narrative Review

Fellow 潘恆之 /VS 鄭昌錡

outline
Outline

Introduction

EPO resistance

New anemia

therapies

introduction
Introduction
  • Definition of anemiain CKD:

Hgb <13.5 g/dl for male; Hgb <12.0 g/dl for female

  • Erythropoietin-stimulating agents:
    • Recombinant human erythropoietin was introduced as a treatment for the anemia associated with chronic kidney disease (CKD) since 1989.
    • Erythropoietin therapy rendered many patients free of blood transfusions with dramatic benefits on quality of life (particularly physical capacity) and other physiologic effects of increasing hemoglobin levels from ~6 g/dL up to approximately 11-12 g/dL.
introduction1
Introduction
  • Several studies showed that partial correction of anemia (to hemoglobin levels in the range of 10-12 g/dL) was a safer strategy, reducing the risk of increased arterial and venous thromboembolism and other possible harmful effects in CKD patients.

Rajiv Agarwal, ClinJ Am SocNephrol, 2010 (5): 1340–1346

slide5

erythropoiesis

  • Hb>13 g/dL

CV risk

Mortality

Stroke

Vascular access thrombosis

slide6

Naturally Occurring Higher Hemoglobin Concentration Does Not Increase Mortality among Hemodialysis Patients

Goodkin D A et al. JASN 2011;22:358-365

  • Among 29,796
  • HD patients in 12
  • nations
  • 545 Endogenous
  • EPO patients
  • were included in
  • each model.
  • Adjusted risk of
  • mortality does not
  • differ significantly
  • for Endogenous
  • EPO patients
  • compared with
  • Other patients(

RR, 0.81; 95% CI, 0.66 to 0.98

RR, 0.98; 95% CI, 0.80 to 1.19

RR 0.94 (95% CI, 0.72 to 1.22

slide7

Effect of erythropoietin levels on mortality in old age: the Leiden 85-plus study

den Elzen W P et al. CMAJ 2010;182:1953-1958

  • Cumulative all-
  • cause mortality
  • among 428
  • CKD 1~2 patient
  • aged 86 at
  • baseline, by
  • tertileof
  • erythropoietin
  • level at
  • baseline
  • (lowest = 3.4–
  • 8.6 IU/L, middle
  • = 8.7–12.3 IU/L,
  • highest = 12.4–
  • 103.0 IU/L).
  • Higher concentration of endogenous EPO => fatal outcome ↑
  • Excessive EPO synthesis => off-target biological consequences ↑ ??
  • Limitations: undiagnosed hypoxemia? Impaired bone marrow response?
  • EPO resistance?
slide8

Association of Mean Weekly Epoetin Alfa Dose with Mortality Risk in a Retrospective Cohort Study of Medicare Hemodialysis Patients

Am J Nephrol 2011;34:298–308

  • The cohort included 137,918
  • HD patients. Mean age was
  • 63.2 years
  • Relative hazards of death
  • over mean EPO dose per
  • week during 3-month
  • exposure period, in patient-
  • months with mean
  • hemoglobin
  • The distribution of mean EPO
  • dose per week is displayed in
  • the shaded area, and the
  • referent dose is shown by
  • thesolid vertical line.
slide9

Review

Pattern of resistance to erythropoietin-stimulating agents in chronic kidney disease

Oluwatoyin F. Bamgbola, Kidney international (2011) 80, 464-474

  • Uremic toxins/Oxidative stress/
  • Inflammation
  • Nutrition deficiency
  • Heavy metal
  • Hematologic disorders
  • Angiotensin-modulating agents
  • EPO inhibitors
slide10

Erythropoietin-stimulating agents (ESA) resistance:

Hb < 11g/dL over 3 month despite of EPO

dose > 400 IU/kg/wk or 20000 IU/wk (≥1.0μg/

kg for darbepoietin)

uremic toxins
Uremic toxins
  • The mechanism is uncertain
  • There is fair correlation of urea nitrogen clearance with improved cytokine profiles (IL-6, CRP) and lower requirement for ESA.
  • Uremia may be related to:
    • Poor bone marrow response to ESA
    • Accelerated turn over rate of RBC from altering erythrocyte

morphology by inducing outward expression of the

phosphatidyl-serine content of its inner membrane

oxidative stress
Oxidative stress

*Oxidative stress

downregulates

the generation

of hypoxic

inducible factor

(HIF) protein.

Haase V H Am J Physiol Renal Physiol 2010;299:F1-F13

inflammation
Inflammation

CKD pro-inflammatory cytokines: IL-6

* Pro-inflammatory cytokines such as IL-1, IL-6, INF-γ, TNF could disrupt iron recycling and absorption

Oluwatoyin F. Bamgbola, Kidney international (2011) 80, 464-474

DMT 1, divalent methyl transporter-1

Process of physiological iron recycling involving macrophages and enterocytes

inflammation1
Inflammation

* Pro-inflammatory cytokines promote EPO resistence by activation of suppressor of cytokine signaling and inhibition of nuclear factor κB

Pro-inflammatory cytokines

(+)

SOCS, suppressor of cytokine signaling; STAT-5 signal transducer and activator of transcription-5

Oluwatoyin F. Bamgbola, Kidney international (2011) 80, 464-474

Erythropoietin receptor activation and intracellular signal transduction

inflammation2
Inflammation
  • Failed allograft – nephrectomy is a reasonable approach for transplant rejection with persistent elevation of inflammatory indices and intractable anemia.
  • Dialysis catheters – additional sources of oxidative inflammation are the use of per-cath and synthetic grafts as vascular access in HD subjects.
nutrition deficiency
Nutrition deficiency

1. Iron

2. Folate

3. Vitamin C

nutrients deficiency
Nutrients deficiency
  • Iron
    • Principally due to poor diet, frequent blood sampling and high frequency of infection
    • Annual loss of 2g of elemental Fe among HD patient
    • Diagnosis: serum iron < 100 mg/dl, TSAT <20%, and serum Ferritin < 100mg/dl ~ at least 2 indices
    • Treatment:

1. Iron therapy

2. Vit-C – mobilize iron from RES

nutrients deficiency1
Nutrients deficiency
  • Folate
    • Principally due to poor gastrointestinal absorption, poor diet, water-soluble nutrient loss, and high catabolic status
    • An essential ingredient for nucleotide synthesis, DNA repair, and re-methylation of homocysteine
    • Folic acid deficiency produces oxidative vascular injury by potentiating uremic inhibition of homocysteine catabolism
nutrients deficiency2
Nutrients deficiency
  • Vitamin C
    • A cofactor for several enzymatic metabolism
    • Promotes GI absorption of iron and enhances its mobilization from RES.
    • Increases Hb synthesis by facilitating incorporation of Fe into protoporphyrin
    • An anti-oxidative free oxygen scavenger, downregulates hepatic synthesis of cytokines
    • Greater loss of Vit-C in HD compared with PD
heavy metal

1. Aluminum

2. Cadmium

3. Lead

4. Mercury

Heavy metal
heavy metal1
Heavy metal
  • Bone marrow function is often impaired in individuals with heavy metal poisoning
  • Aluminum toxicity – P-binder, dialysate,poor control of pharmaceutical standards
  • Cadmium, lead, mercury – industrial pollution, some folk remedies of Indian and Middle Eastern origins
heavy metal2
Heavy metal
  • Lead toxicity is more likely to occur in patient with CKD due to:
    • Iron and calcium deficiencies => GI absorption 
    • Uremia may increase mobilization of lead from bone

tissue stores

  • Lead toxicity causes anemia by precluding incorporation of iron into a protoporphyrin ring for heme synthesis
hematological disorders
Hematological disorders
  • The mechanism of EPO resistance includes bone marrow infarction, hemolysis, hypersplenism, and ineffective erythropoiesis.
  • Common chronic hemolytic conditions are auto-immune diseases, sickle cell disease, thalassemia, hereditary spherocytosis, glucose 6-phosphate dehydrogenase deficiency.
hematological disorders1
Hematological disorders
  • Autoimmune hemolytic anemia occurs in 5-10% of patient with SLE. It is frequently associated with renal or neurological involvement.
  • As reticulocytosis is common in patients on ESA therapy, early diagnosis of hemolytic events may be missed.
  • It should be suspected when there is a progressive increase in EPO requirement while there is rapidly decreasing Hbconcentration withmegakaryocytic cell lineand serum titer of anti-DS DNA.
angiotensin modulating agents1
Angiotensin-modulating agents
  • The influlence is controversial.
  • A prototype study showed there is a higher EPO requirement in dialysis hypertensive patients who were treated with ACEI/ARB compared with CCB.
  • ACEIsuppresses the enzymatic degradation of N-acetyl-seryl-aspartyl- lysyl-proline (AcSDKP), a naturally occurring inhibitor of erythropoiesis.
  • Stimulation of erythroid cellular proliferation by angiotensin binding of its type II surface receptor is inhibited by ARB

=> therapeutic use of ARB in post-transplant

erythrocytosis.

circulating epo inhibitors1
Circulating EPO inhibitors
  • Circulating EPO inhibitors may result in pure red cell aplasia.
  • Pure red cell aplasia should be suspected:

1. Received ESA therapy for 44 weeks

2. Rapid decrease in Hb mass (> 0.5 g/dl per week),

3. Reduction in absolute reticulocyte count <10, 000/

ml and/or 1U of RBC transffusion per week

4.Leucocytes and platelets are normal.

5. The more common causes of EPO-resistant

anemia should be excluded.

circulating epo inhibitors2
Circulating EPO inhibitors
  • Diagnosis:

1. Absence of erythroid precursors on bone marrow

sample and low EPO content of the serum.

2. The serum sample inhibits growth of erythroid

colonies in a bone marrow culture.

3. Radioimmunoassay identifies circulating neutralizing

anti-EPO IgGin serum

  • Treatment:

1. Discontinuation of rhEPO

2. Steroid and/or calcineurin inhibitor

3. Plasma exchange and/or allograft transplantation

secondary hyperparathyroidism
Secondary hyperparathyroidism
  • There is a higher prevalence of anemia and greater EPO requirement HD subjects who are in the upper 50th percentile of intact parathyroid hormone.
  • As a proof of causal relationship, surgical parathyroidectomy led to an improved control of anemia and a lower need for ESA
  • Nevertheless, there is no evidence for a direct inhibition of erythropoiesis by excessive PTH.
1 25 vitamin d deficiency
1,25-vitamin D deficiency
  • Vit-D may have synergistic effect on ESA control of anemia
  • Calcitriol treatment in subjects with uremic bone disease increases the proliferation of erythroid precursors.
  • Lower EPO requirement among subjects with BB gene of vitamin D receptor genotype compared with those with the Bb/bb gene.
potential pharmacological intervention in epo resistance
Potential Pharmacological intervention in EPO resistance
  • Anti-inflammatory agents
  • Nutritional supplements
  • EPO-mimetic peptide
  • Endogenous induction of EPO
slide37

Narrative Review

New anemia therapies: Translating Novel Strategies From Bench to Bedside

Iain C. Macdougall, Am J Kidney Dis. 2012;59(3):444-451

  • EPO-mimetic peptide
  • HIF Stabilization
  • Hepcidin Modulation
  • GATA-2 Inhibitors
  • EPO gene therapy
epo mimetic peptide1
EPO-mimetic peptide
  • The concept that a peptide could activate the erythropoietin receptor and stimulate erythropoiesis was described first by Wrighton et al in 1996 in Science.
  • EMP-1 (erythropoietin-mimetic peptide 1) was able to stimulate cellular proliferation of erythroid cells in a dose-dependent manner and also increase reticulocyte counts in animal models.
  • However, EMP-1 had low affinity for the erythropoietin receptor and low biological activity.
epo mimetic peptide2
EPO-mimetic peptide
  • Peginesatide is a dimeric peptide joined with a spacer linker to a pegylation chain to enhance its metabolic stability in vivo.
  • No structural homology between peginesatide and erythropoietin. Antibodies against erythropoietin do not cross-react with peginesatide, and vice versa.

=> potential therapeutic use for pure red cell aplasia

Iain C. Macdougall, Am J Kidney Dis. 2012;59(3):444-451

peginesatide phase 3 clinical trials overview
Peginesatide Phase 3 Clinical Trials Overview

Iain C. Macdougall, Am J Kidney Dis. 2012;59(3):444-451

regulation of hypoxia inducible factor hif activity
Regulation of hypoxia inducible factor (HIF) activity

HIF stabilization

Iain C. Macdougall, Am J Kidney Dis. 2012;59(3):444-451

hif stabilization1
HIF Stabilization
  • Prolyl hydroxylase inhibitors
    • Advantages –

1. Orally active

2. Modulate other genes involved in erythropoiesis in

addition to the EPO gene.

    • Disadvantages –

1. Upregulate several hundred other hypoxia-sensitive

genes, including those involved in glucose regulation,

angiogenesis, such as VEGF (vascular endothelial

growth factor)

=> enhance tumor growth or proliferative diabetic

retinopathy ??

hif stabilization2
HIF Stabilization
  • The first-generation HIF stabilizer molecule (prolylhydroxylase inhibitors) -- FG 2216

=> Patients developed abnormal liver enzymetest results,

and one developed fatal hepatic necrosis in phase 2

clinical trial

  • The second-generation HIF stabilizer molecule – FG 4592

=> Significantly increase Hctand decrease serum Hepcidin levels

=> This is now in phase 2 clinical trial.

hepcidin modulation1
Hepcidin Modulation

* Hepcidin inhibits

ferroportin,

which controls

iron efflux from

duodenal

enterocytes,

hepatocytes,

and macrophages

* Uremia is a

chronic

inflammatory

state. Dialysis

patients have

much higher

serum hepcidin

levels.

Babitt JL, Molecular mechansms of hepcidin regulation: implications for the anemia of CKD. Am J Kidney Dis. 2010 (55):726-741

hepcidin modulation2
Hepcidin Modulation
  • Strategies:
    • Monoclonal antibody against hepcidin (NOX-H94)has been shown the effect on inhibition of IL-6 induced anemia in mouse models.
    • Inhibition of the hepcidin production by using antisense oligonucleotides or sliencing messenger RNA transcribed from the hepcidin gene(HAMP)
  • None of the strategies have been subjected to clinical trials.

=> Hepcidinhas antimicrobial properties. Inhibition of

hepcidin might exacerbate the risk of infection ?

gata 2 inhibitors1
GATA-2 Inhibitors
  • GATA-2 inhibitors: K-7174 and K-11706.

GATA-2

inhibitor

Iain C. Macdougall, Am J Kidney Dis. 2012;59(3):444-451

Imagawa S. Negative regulation of the erythropoietin gene expression by the GATA transcription factors. Blood. 1997(89):1430-1439

gata 2 inhibitors2
GATA-2 Inhibitors
  • K-11706 was found to evoke greater hypoxic induction compared with K-7174, possibly through stimulation of HIF-1 binding activity in addition to GATA inhibition.
  • Potential role for an orally administered GATA inhibitor in the treatment of anemia.

Imagawa S. Negative regulation of the erythropoietin gene expression by the GATA transcription factors. Blood. 1997(89):1430-1439

erythropoietin gene therapy1
Erythropoietin Gene Therapy
  • In 2005, a group of Israeli scientists developed a functional delivery system for the EPO gene using skin cells on SCID mice (using adenovirus vector).
  • The mice responded by producing increased levels of erythropoietin, and this was associ- ated with an increase in hematocrit. No such effect was seen with the vector alone.
erythropietin gene therapy
Erythropietin Gene Therapy
  • In 2010, a small group of patients with CKD in Israel have taken part in a proof-of-concept phase 1-2 clinical trial of this delivery system for the EPO gene.
  • All patients showed increased erythropoietin production, with most showing sustained eleva- tion of hemoglobin levels (the primary end point) in the target range of 10-12 g/dL for 6-12 months without receiving additional erythropoietin injections.
conclusion1
Conclusion
  • It took us nearly 20 years to realize the limitations of ESAs and the potential for harm if used too aggressively.
  • This review summarizes our current knowledge about a variety of new strategies for stimulating erythropoiesis.
  • They will need to be subjected to the same degree of scientific investigation as the existing ESAs, and it may be many years before the true efficacy-safety balance of these novel scientific strategies is realized.
clinical evaluation of resistance to erythropoietin stimulating agent in chronic kidney disease
Clinical evaluation of resistance to erythropoietin stimulating agent in chronic kidney disease

Al toxicity

Pb toxicity

Cu deficiency

Hypothyroidism

Oluwatoyin F. Bamgbola, Kidney international (2011) 80, 464-474