ESAs are widely used agents to manage CKD-related anemia. ESA resistance, or , is a definition used to recognize ptns not achieving their target
EPO Hyporesponsiveness
Abbreviations:
o A/V: arteriovenous.
o ACEi: angiotensin-converting
enzyme inhibitors
o AMI: myocardial
infarction.
o ARBs: angiotensin II receptor
antagonists.
o CHOIR: Outcomes in Renal
Insufficiency trial
o CKD: chronic kidney disease.
o CVS MR: cardiovascular mortality.
o Depoa: Darbepoietin a.
o DX: dialysis.
o Dzt: dialysate.
o EPO: erythropoietin.
o ESAs: erythropoiesis-stimulating
agents.
o ESKD: end-stage kidney disease.
o HB:
Hemoglobin.
o Hct: haematocrit.
o HDX: haemodialysis.
o HIV: human immunodeficiency
virus infection
o Hrsp hyporesponsiveness
o KDIGO: Kidney Disease: Improving
Global Outcomes.
o KDOQI: The Kidney Disease
Outcomes Quality Initiative.
o MM: multiple myeloma.
o OFC: osteitis fibrosis cystica
o PD: peritoneal dialysis.
o PRCA: Pure red cell
aplasia.
o TREAT: Trial to Reduce
Cardiovascular Events with Aranesp Therapy study
o URR: urea reduction ratio.
ESAs are widely used agents to manage CKD-related anemia. ESA resistance, or (Hrsp), is a definition used to recognize ptns not achieving their target HB levels despite the administration of higher doses of ESAs or requiring persistently higher ESA doses to preserve their HB levels. ESA resistance is
generally relative rather than complete. ESA resistance is also referred to as Hrsp. The criteria of ESAs resistance still not well determined. KDOQI criteria include failure to achieve/maintain a target HB with a maximum dose of 450 units/kg/wk IV EPO or 300 units/kg/wk SC EPO. Criteria of Depoa & methoxy
polyethylene glycol-epoetin beta, not well defined
yet, as the exact dose conversion is not well-determined. Package inserts include:
45,000 units/wk
of epoetin corresponds roughly to 100 mcg/wk of Depoa. Other criteria given by European
Best Practice Guidelines & KDIGO may include the following:
1)
Failure to attain or maintain desired HB with 300 units/kg/wk of EPO (= 20,000 units/wk)
& 1.5
mcg/kg/wk of Depoa (about 100
mcg/wk).
2)
Lack of rise in HB after 1st mo of proper weight-based dosing and/or requiring 2 rises in EPO dosage up to 50 % above the original
dose in a stable ptn. Also, EPO-resistant = higher dose requirement than that given to 90 % of other ptns.
EPIDEMIOLOGY: retrospective report: ESA Hrsp = 2
consecutive HB levels <10 g/dL with EPO >7700 units/dose,
in 12.5 % of HDX ptns. ESA resistance in PD has not been well identified but much less commonly seen than HDX ptns as PD ptns usually show
higher HB levels, requiring
less ESA dosages.
Aetiology: the 2 most common factors: Iron deficits & infection and/or inflammation
1)
Iron
deficiency: commonly seen
cause of EPO resistance. It
could be “absolute” (e.g., external
blood loss) or “functional” (related to EPO or anemia of CKD). EPO resistance assessment
should include both categories of iron deficiency.
2)
Infection/inflammation: Chronic inflammatory states are commonly seen in HDX and are crucial causes of EPO resistance. DX catheter is a
common cause of chronic inflammation. Other causes may include skin/wound
infection; failed KTx; hidden
infected old, non-functioning A/V graft; and HIV infection.
3)
Inadequate
DX: Old study: 20
stable HDX ptns moderately
under-dialyzed (mean URR: 60.7 %), augmenting DX dose has led to raised Hct with the same dose of EPO. Difference in DX membrane can impact EPO response as expanding urea clearance can be achieved by providing larger
dialyzer with a better membrane.
4)
Increasing DX dose is not likely
to increase EPO response in ptns
with fairly adequate DX (i.e., Kt/V ≥1.0-1.2). Only changing
in DX modality may impact
EPO response. Providing
ultrapure Dzt can improve HB & decreasing EPO needs that can be explained by a limited inflammatory process (Ultrapure
Dzt = properly maximized
micro-biological purification).
5)
Other: causes may include severe hyperparathyroidism with OFC, bone aluminium intoxication (rare), cancer, bone marrow diseases e.g.,
myelodysplastic syndrome, MM, and hemoglobinopathies, e.g., sickle cell disease, B12 & folate deficits.
6)
PRCA, can induce complete EPO resistance, seen with SC EPO, no longer seen.
ACEi/ARBs may induce
relative EPO resistance (genetic
background assumed).
SUGGESTED APPROACH: It is recommended to
assess EPO-resistant cases thoroughly
as EPO resistance is commonly associated
with higher MR:
o Exclude absolute &
functional iron deficiency and manage accordingly.
o Assure adequate DX, modify DX prescription
to achieve appropriate Kt/V.
o Thorough physical testing
to exclude hidden infection, esp. thrombosed A/V graft.
o Observational studies: old graft excision leas to better EPO response. Also does HDX catheter removal with A/V fistula placing improve EPO response.
o Severe hyperparathyroidism:
optimize PTH levels either
medical or surgical. Hyperparathyroidism control will improve EPO response.
With persistent EPO resistance, EPO can be held or continued with low doses to limit
transfusion requirement that can be provided to limit anemia-associated Sms. New agents
of ESA in
DX ptns
resistant to EPO needs more
evaluations. Non-iron factors have been assessed as EPO
adjuvants e.g., L-carnitine, ascorbic acid, pentoxifylline.
OUTCOME
Mortality: ESA resistance
can be associated with higher MR. Observational
study: HDX ptns (US), ptns with HB <9.5 g/dL + higher ESA dose increments along 11-mo duration showed
higher MR
risk. Another study: data from the “Normal Hct Cardiac
Trial”, a higher EPO-responsiveness
measure (= ratio of weekly Hct alteration per ESA dose rise) a lowered MR
has been observed. The impact of EPO resistance
on MR with PD is not well assessed. Korean study: EPO resistance was associated with increasing MR with HDX
but not with PD ptns. However, other reports comparing HDX with PD have not assured this link.
The higher MR seen with EPO resistance could
be attributed to the underlying factor of EPO resistance. However, some reports assumed that the higher MR could be attributed to the higher EPO doses provided to these ptns. Unadjusted analysis of the Corrected
HB in the CHOIR study, the higher risk of the primary endpoint (death, AMI, HF, or stroke)
at 4 mo. was
related to both the inability to achieve targets and the high doses of EPO administration (>20,000 units/wk).
On the other hand, adjusted analysis: only
higher doses of EPO agents resulted in an independent higher risk of
the primary endpoints. This elevated risk was seen in both high- &
low-target HB groups, especially
among ptns unable to achieve target HB. Whilst most reports were focusing on Hrsp during
ongoing chronic EPO therapy, the
relation between primary HB response
to Depoa was evaluated
in the TREAT trial. Ptns not responding
to the 1st 2
doses of Depoa had higher rate of
CVS endpoint
& death as compared to those with a better initial therapeutic response.
Meta-regression
analysis: 31 trials (12,956 ptns):
all-cause MR was associated
with elevated 1st 3-mo. & total-study-duration mean EPO doses independent of HB level. A similar trending for CVS MR that was statistically insignificant. The elevated total-study-duration
mean ESA dosing was
associated with a higher rate of HT, stroke, and thrombotic sequelae, including A/V vascular access-related thrombotic sequelae. However,
the associated increased ESA dosing to MR has not been observed
in all reports. Observational report: older HDX ptns, EPO dosing > 30,000 units/wk
were NOT associated with any harm or benefit.
Progression of CKD: EPO resistance
could be complicated by more rapid progress to ESKD.
Study: 194 consecutive CKD ptns started EPO between 2002 & 2006. Ptns were categorized
as poor, intermediate,
& good responders according to
the response to the 1st provided EPO dose. Responsiveness was assessed according to
the formula: (Hb1-Hb0)/time/EPO dose where Hb1 and Hb0
correspond to HB values at the 1st
visit after given EPO and at baseline, resp; time refers to the duration
between visits; and EPO dose is the 1st weekly provided dose. ESA responsiveness was expressed as g/dL/mo.,
standardized to 10
mcg/wk. During a medium following-up for 3
y., poor responsiveness was complicated by an increased risk of ESKD. The underlying mechanism still uncertain.
COMMENTS