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).

 Fordiagnosis 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 Hb
values.

 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
 Accelerationof 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 EPO

PHD of ODD

Adequate O2
VHL
 Relative EPO deficiency.
 Shortened RBC survival
 Bone marrow suppression.
 Other substrate deficiencies(B12 and folic
acid)
 Iron deficiency.
 Blood loss
 “hemopoietine”

 30.4kDa glycoprotein hormone, plays a

central role as a growth factor that sustains
the survival of erythroid progenitor cells.

 Primarysite of production is the liver in the

fetus and kidneys after birth.

 Major sites of production-peritubular

capillary endothelial cells and peritubular
fibroblasts.
 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.
 Diagnosisof anemia should be made and
further evaluation should be initiated once
Hb is <13.5g/dL for males and <12g/dL for
females.

 Thisdefinition 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/mL
in 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.

 Theaverage 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
 Hblevels 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
 Twolarge 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.

 Thehigh 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 alfa
when 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.

 ESAand iron supplementation forms the core

of anemia management and has to be
understood in detail.

 Thedata on the upper limit of target Hb is

conflicting but there is a trend towards a
lower value.