Dr. Vishal Golay

22/07/2011

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

Alonzo Mourning

Richard Bright (1836): first observed that anemia was a complication of renal failure.

Robert Christison: further described renal anemia.

Miyake (1977): purified and identified erythropoietin.

Eschbach (Dec 2, 1985): first human use of EPO

Burden of anemia in CKD.

Effects of Anemia in patients with CKD.

Normal Erythropoiesis and Causes of anemia

in CKD.

ESA and Iron therapy.

Evaluation of patients.

Treatment.

Controversies

Anemia is a condition in which the number of

RBCs or their oxygen-carrying capacity is

insufficient to meet physiologic needs, which

vary by age, sex, altitude, smoking, and

pregnancy status (WHO).

For diagnosis and further evaluation Hb

values according to NKF guidelines:

• <13.5 g/dL in adult males. (WHO-13g/dL)

• <12.0 g/dL in adult females.

According to the NHANES III data, the drop in Hb was

significant in males whose GFR dropped below 75ml/min

and females whose GFR dropped below 45ml/min

68

51.5

-5

Curr Med Res Opin 20:1501-1510, 2004

Many studies that examined the relationship between Hb level and kidney function:

Have been cross-sectional and not longitudinal in design.

Described patients entered into clinical trials or seen by nephrologists, which are not a truly representative sample of patients with CKD.

Included small numbers of patients with lower levels of kidney function.

Used a great variety of methods to assess level of kidney function. It therefore is difficult to determine whether the variability in Hb at levels of kidney function is caused by variability in measurements of kidney function or variability associated with CKD itself.

Used the MDRD4 formula to estimate GFR, the precision of which decreases at higher levels of kidney function.

Did not describe the cause of the anemia in patients with CKD.

KDOQI 2006

QUALITY OF LIFE:

Anemia results in poorer quality of life in patients with renal failure.

This correlation can be proven by the poor quality of life scores in patients with lower Hbvalues.

Many observational as well as RCT have positively demonstrated that the QOL scores improved in patients who were given ESA and iron to increase their Hb

Generation of hypoxia due to anemia is poorly

tolerated in patients with preexisting cardiac

and vascular diseases. Compensatory

mechanisms leads to development of LVH.

Observational studies do show an increase in

mortality in patients with CKD but not direct

casualty.

Interventional studies (DOPPS) show that for an

increase of 1g/dL of Hb results in 4% decline in

mortality.

Also, Medicare data show that CKD=100% and

CKD+Anemia=270% in 2-yr mortality risk.

CV disease related mortality is 15 times more

in patients with CKD.

50% of deaths in patients with CKD are due to

CV disease.

LVH is the most common abnormality seen in

patients with CKD and there is a strong

correlation between anemia and LVH.

Tissue hypoxia due to anemia is the principal

stimuli triggering the compensatory changes

that stresses the CV system

Acceleration of progression of kidney

disease by oxygen deprivation.

Increased risk of bacteremia (11% increased

risk for every 1g/dl fall in Hb)

Detrimental effects on brain and cognitive

functions.

Degradation

Hypoxia HIF-1a HRE EPOPHD of ODD

Adequate O2VHL

Relative EPO deficiency.

Shortened RBC survival

Bone marrow suppression.

Other substrate deficiencies(B12 and folic

acid)

Iron deficiency.

Blood loss

“hemopoietine”

30.4 kDa glycoprotein hormone, plays a central role as a growth factor that sustains the survival of erythroid progenitor cells.

Primary site of production is the liver in the fetus and kidneys after birth.

Major sites of production-peritubularcapillary endothelial cells and peritubularfibroblasts.

Normal levels-10-30U/L

1 unit of EPO=erythropoietic effect in animals as occurs after stimulation with 5µmol of cobalt chloride.

The EPO-receptor is a transmembrane receptor that belongs to the cytokine receptor superfamily.

Receptor undergoes homodimerization after binding to EPO triggering downstream pathways(Ras/MAPk, JNK/MAPk, JAK/STAT and PI3.

This activation promotes increased survival of precursor cells.

EPO levels may be same or higher in patients

with CKD than in normal nonanemic persons.

Concept of relative EPO deficiency.

Relationship between EPO and Hb depends

on the severity of renal failure.

The measurement of EPO levels in CKD is not

helpful for making the diagnosis of anemia.

Diagnosis of anemia should be made and further evaluation should be initiated once Hb is <13.5g/dL for males and <12g/dL for females.

This definition represents the mean Hb of the lowest fifth percentile of the sex-specific general adult population

This is different from the WHO definition (due to the different patient data used for making the recommendations)

Preliminary investigations: CBC with PBS (sampling in HD-CKD patients should be

timed to midweek predialysis)

Red cell indices

Further evaluation of cause of anemia should be based on the findings of CBC.

Reticulocyte count and its corrections (index and RPI)

Serum Iron Profile.

Causes of anemia other than EPO deficiency should

be considered when

the severity of anemia is disproportionate to the impairment of renal function,

there is evidence of iron deficiency, or

there is evidence of leukopenia or thrombocytopenia.

KDOQI 2006

Anemia

Guidelines

KDOQI recommends using ferritin and TSAT or CHr

The evaluation of the cause of anemia should always precede initiation of ESA.

Iron status evaluation serves two purposes:

To assess the potential of contribution of iron deficiency

To direct further evaluation for GI blood losses

Use of iron indices for following up therapy is not very clear.

In ND-CKD, ferritin levels less than 25 ng/mLin males and less than 12 ng/mL in females suggest that storage-iron depletion is contributing to anemia.

However in HD-CKD, ferritin is less reliable

Iron-deficiency erythropoiesis is most likely to contribute to anemia when TSAT results are less than 16%.

However, the clinical utility of TSAT is impaired by the absence of a diagnostic threshold.

rHuEPO was genetically modified proteins that were very similar to the nascent EPO.

Contained the 165AA backbone with one O-linked and three N-linked gycosylated chains.

There gycosailylated chains contain variable amounts of sialic acid residues.

Many forms of rHuEPO are available: Alfa, beta(NeoRecormon, Roche), omega, delta(Dynepo), pegylated forms

Methoxy polyethylene glycol-epoetin beta is

made from erythropoietin by chemically

linking the N-terminal amino group or the Є-

amino group of any lysine present in the

protein with methoxy polyethylene glycol

butanoic acid.

The average molecular weight is

approximately 60kDa

Marketed as Mircera (Roche)

Hematide: Novel peptide ESA which is not structurally related to

EPO but mimics the propertied of EPO.

currently in phase III of its clinical development program.

Properties unique to hematide are: greater ex vivo stability, a prolonged pharmacodynamic action, a different

immunogenicity profile with no cross-reactivity between Hematide and anti-EPO antibodies, and a simple manufacturing process involving synthetic peptide chemistry.

HIF stabilizers

GATA inhibitors

Oral formulations (sulfate, gluconate, fumarate,

polysaccharide complex)

Parenteral (iv) formulations (dextran, gluconate, sucrose,

ferric carboxy maltose).

In patients with HD-CKD iv formulations are the only form to

be used (KDOQI)

Newer formulations are associated with significantly fewer

side effects.

The exact schedule for delivery needs to be optimized for

each patient and there should be regular monitoring of Fe

stores.

Iv iron therapy should be guided by the iron status of the

patient rather than empirical Rx. Approx 1000mg of Fe over

2-3 weeks is necessary to overcome the deficiency

Hb levels should be monitored at least once

a month during ESA therapy (KDOQI-2006)

Target rise of Hb should be in the range of 1-

2g/month.

Iron profile should be done at least once a

month during the initial period of therapy

and then one every 3 months during the

maintenance phase

Normal Hematocrit Cardiac Trial (1998):

suggested that attempts to normalize

hematocrit in hemodialysis patients was

associated with harm.

KDOQI(1991): Hb targets of 11-12g/dl

Many observational studies were published

after that which showed better outcomes

with higher Hb targets and so this upper limit

was liberalized

KDOQI 2006

Anemia

Guidelines

Two large RCT’s CHOIR and CREATE were

published in November 2006 showing no

benefit in one (CREATE) and harm in the

other (CHOIR) with respect to cardiovascular

outcomes in subjects randomized to a higher

target hemoglobin level.

The high burden of cases and the cost

involved in maintain higher Hb levels was the

main trigger for continuous debate on the

adequate upper limit o

randomized, double-blind, placebo-controlled trial conducted at 623 sites in 24 countries.

4038 patients with diabetes, chronic kidney disease, and anemia, we randomly assigned 2012 patients to darbepoetin alfa to achieve a

hemoglobin level of approximately 13 g per deciliter

2026 patients to placebo, with rescue darbepoetin alfawhen the hemoglobin level was less than 9.0 g per deciliter.

The primary end points were the composite outcomes of death or a cardiovascular event (nonfatal myocardial infarction, congestive heart failure, stroke, or hospitalization for myocardial ischemia) and of death or end-stage renal disease.

The use of darbepoetin alfa (to achieve a higher Hb

target) in patients with diabetes, chronic kidney

disease, and moderate anemia who were not

undergoing dialysis did not reduce the risk of either

of the two primary composite outcomes (either death

or a cardiovascular event or death or a renal event)

and was associated with an increased risk of stroke.

This risk may outweigh the potential benefits.

The current evidence, based on mortality data, for hemoglobin target levels intentionally aimed with ESA treatment in CKD patients treated indicates that

levels of >13 g per 100 ml can be associated with harm,

levels of 9.5–11.5 g per 100 ml are associated with better outcomes compared with >13 g per 100 ml

for levels between 11.5 and 13 g per 100 ml, there is no evidence at this time for harm or benefit compared with higher or lower levels.

Locatelli et al, Kidney Int; July 2008

Anemia is a significant contributor to

mortality and morbidity in CKD.

ESA and iron supplementation forms the core

of anemia management and has to be

understood in detail.

The data on the upper limit of target Hb is

conflicting but there is a trend towards a

lower value.