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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.