Q.396. How to start work up for Epo resistance?
ERYTHROPOIETIN THERAPY
Revise please the abbreviation list on:
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Q.396. How to start
work up for Epo resistance?
A. Work up for Epo resistance:
1) Iron deficiency: the
most common cause of
resistance, either due:
i. Increased losses. or
ii. Incr.
consumption. So, confirm adequate stores by (TSAT & s.
ferritin). * Revise source of losses: [Dzer- G.I.- phlebotomy-Dx. session.].
2) 2ry hyperpara: A correlation exists between Epo. requirement &
i. iPTH level.
ii. Degree of B.M. fibrosis.
iii. Osteoclastic & eroded surface é bone biopsy.
- PTH.🠞Direct inhibitory
effect é RBCs proliferation.
- Vit. D.🠞Improves
Erythropoiesis, in
a way apart fr. its effect on PTH level.
- Vit. D.🠞Growth f.🠞enhances resp. to Epo, apart
fr. its effect on PTH level.
3) Aluminum toxicity: Rare, since application of (AAMI) (Standerd Association é Advance in Medical Instructions).
*** Mechanism of Aluminum Toxicity: Competition
between (Alum.) & (Iron) for binding to “transferrin”, before substrate delivery to erythropoietic
element & interfere é enzyme insertion of iron into heme
moiety at closure of the tetra pyrole ring
or with heme synthesis itself.
4) H.B.pathies & Hemolytic anemias: Sickle cell🠞🠝Dose req. of Epo &🠝F.H.B.
-“Chloramine” of city
water🠞🠝Epo req., So, use carbon to dcr. chloramine
& to dcr. A.B.(anti-N. form)
production, after subclinical exposure to formaldhyde.
-“Lipid peroxidation” 🠞Hemolysis🠞🠝Epo requirement.
5) Folate & B12 deficiency🠞essential co-factor or supplements.
6) Multiple myeloma: (B cell dyscrasia,
No C.I. to EPO thpy).
7) Inflammation: Interaction between “Cytokines” & B.M. elements 🠞dcrease Epo response .
**The proinflammatory cytokines é B.M. level, esp. [TNFa, I.L.1,6, INF. g ] 🠞
1. Growth
of “erythroid
progenitor” cells.
2. 🠋“Local response” to Epo.
3. Increased
TNF production🠞Increase resistance to Epo.
8) Carnitine deficiency: see Q. 397.
9) ACE: see Q. 398.
10) Effect of delivered DX. dose & membrane: Resp. to Epo increased é :
1. 🠝 DX. dose.
2. Bicarbonate DX.
3. Membrane
é sp. anti-oxidant. Vit. E modified membrane 🠞🠝 small & middle molecule clearance 🠞🠝 Resp. to Epo.
11) Anti-Epo A.B. 🠞 see Q. 403.
12) Individual “B.M.” sensitivity
to rHuEpo: Ptn.
who need 🠝500 i.u./kg/w.,
or
fail to maintain Hct ≥ 30, probably hv underlying inflmm./ infc..
13) (X)
Peginesatide: [a synthetic peptide tht activates
EPO receptor & stimulates
RBCs production], but because its amino acid sequence is unreal-ted to Epo.,
does not cross react é EPo A.B. On the basis of two completed rando-mized
trials, FDA has approved peginesatide for i.v./s.c. routes for ttt. anemia in
adult DX. Ptn.s but not in CKD ptns who are not on DX or in ptn é cancer-related anemia. Role of Peginesatide in DX.
is not known as yet, but it may be effective
in treating ptn. who are hyporespons-ive to available erythropoietic ag.s bec.
of circulating anti-EPO A.B..
N.B. Affymax, Inc. along é FDA
: Voluntary recall of all lots of OMONTYS® (peginesatide) inj. to the user level due to postmarketing
rep. incl.: serious
hypersensitivity reactions, include anaphylaxis, wch cn be life-threatening/fatal. Fatal
reactions hv bn rep. in 0.02 % of ptns. following i.v. 1st
dose, occ. 30 min. after administration. No rep. of such reactions foll.
subsequent dosing, or in ptns. completed their DX session. Since launch,
> 25,000 ptns. hv received Omontys in post-marketing setting.
The rate of overall hypersensitivity reactions is neerly 0.2 %,
one third of these being serious incl. anaphylaxis requiring prompt medical
intervention & hospitalization. Omontys (peginesatide) Inj. is indicated
for ttt. of anemia due to CKD in adult DX. ptns & packaged in 10
& 20 mg Multi-dose Vials. RECOMMENDATION:
DX
organizations are instructed to discontinue use.
Q.397. What is the role of L-Carnitine
deficiency in erythropoiesis?
A.
L-carnitine is an “essential co-factor” for “transmitochondrial
transport” of F.A. for oxidation. It’s depleted by H.DX.,
So, it is essential for:
1) Maintenance of RBCs “membrane
integrity”.
2) Improving RBCs “deformability”.
3) Increasing RBCs “survival
time”.
4) Improving
RBCs “osmotic fragility”. +
5) Improving
“dyslipidemia”.
- In U.S., Only Two ✌ valid indications for
“L-carnitine”:
1. Epo resistance, in absence of other evidences.
2. Refractory intradialytic
hypotension.
Q.398. What is the relation of ACEI to anemia ?
A. A relation between ACEI & 🠋H.B.
co-exists, as:
1) ACEI 🠞🠋testosterone in ♂.
2) ACEI (ACE🠞degrade
ACSDKP) 🠞🠝ACSDKP🠞🠋Erythropoiesis (ACSDKP
= N-Acetyl seryl D-aspartyl K-lysyl
Proline) = a
physiological inhibitor of erythropoiesis). أسد كلب
Q.399.What is the therapeutic goals of Epo?
A. K/DOKI 2006:
v *
Minimum target H.B. 🠞11 g/dl. * Maximum🠞13 g/dl.
v *
Canadian: [10.5-11.5] g/dl. *🠝12 g/dl. 🠞Risky
in Canadian protocols.
v N.B. : Only cardiac ptn (CHF & IHD)🠞High mortality é high Hct %. ✽
Q.400. What
are the specific benefits u can get from Epo therapy ?
A. Specific benefits of Epo:
1) Brain & cognitive
functions: Improves
electro-physiological, visual concept, vasomotor,
auditory verbal, symbol digital modality, O2 uptake & brain metab.
2) CVS:🠋 L.V.H., 🠋 L.V.D. & 🠋 cardiac mortality. Epo thpy a L.V. regression. 👍
3) Quality of life: greatly improved. 😃😀
4) Mortality/Morbidity: greatly decreased.
5) Kidney func.: Correction of anemia é Epo ] Retard
progression of R. dis., esp. é non-Dc.s…”Nephron” 1997.* RENAAL study: [Reduction of End-point
Non-insulin dependent D.M., é Angio-tensin II Antagonist,
Losartan]: Low Hct † Poor outcome &prevention
of or amelioration of anemia† Lesser risk
of progression to ESRD.** Kid. 2004: Early ttt. of anemia for CKD, SLOWS decline
in R. function.
6) Complete correction of anemia é Epo therapy: Incr. the whole blood anti-oxidant
capacity, indicating a positive effect on free radical
metabolism.
Q.401. What is the effect of Epo therapy on blood rheology?
A. Epo
c higher H.B. cÇVascular access thrombosis of autologous &
synthetic (graft) A/V access.
Q.402. What is the dose, route & target H.B. of
darbepoietina (Aranesp) therapy?
A. “Darbepoietina therapy(Depo):👍& ”مَاهِيَ الوصَايَا العَشْر :
1) Target HB = 10-12
g./dl in pre-& D.X. Ptn.. Don’t exceed 12 g./dl. 👆
|
|
2) Initial I.V./ S.Q. dose:
D.X.🠞 & Non-D.X. 🠞 0.45 ug/kg/w & 0.75 ug/kg/w resp.
3) Max.
rise: one
g/2w.( 👉(جرامين
في الشهر, for any ptn.
4) I.V. Route for H.DX. ptn. is
preferred.
5) Maintenance: titrate until target (11-12) g/dl.
6) If H.B. approaches 12 g. (or > one g. in 2 w.)🠞 Dcreased
by 25 %.
7) If
H.B. continue rising 🠞Hold Depo. until beginning to decr. , then resume é 25 % of the previous
dose.
8) If H.B. doesn’t increased by one g./4 w. é adequate iron stores 🠞 increased by 25 % .
9) Do NOT
incr. dose more frequently than 4 w. interval.
10) Maintenance Dose:
v Pre-DX.🠞S.Q.: ONCE monthly 🠞10-12 g/dl.
v DX. Ptn.🠞Titrate to target 🠞10-12 g/dl.
Q. 403. What is PRCA (pure red cell aplasia)? How to manage?
Majority of
cases occur é
epoetin alfa. (Eprex). Underlying cause🠞organic
compounds (polysorbate fr. uncoated rubber stoppers in
prefilled syringes)🠞 anti-EPO A.B. All cases (200
rep.) have occur é S.C.Epo. PRCA still extremely rare. After changes in
storage & handling recomm. & discontinuation of s.c. Eprex, incid. of PRCA hs
declined. Screening anti-EPO A.B. is not recomm. in DX. PRCA shd be considered in é signif.
anemia é EPO for at least 3-4 w. & previously
resp. to EPO.:🠞 sudden decline in H.B. despite EPO, severe decrease in Retics & normal WBC & platelet counts.
To diagnose PRCA,
B.M. aspirate &
pres. of neutralizing anti-EPO A.B. shd be
performed. B.M. reveals:
severe erythroid hypoplasia, é < 5 % RBCs precursors & evid. of maturation block of
erythroid precursors. Platelet
& WBCs precursors are entirely normal.
Anti-EPO A.B.
are detected by RIPA,
ELISA. Sample must
be sent to manufacturer for testing anti-Epo A.B. &
their neutralizing ability.
Stop all erythropoietic stimulating ag. & do NOT switch. to another EPO or Dpo.
Ptn. shd be transfused é Sm.tc
anemia. As spont.
remission is rare, start im/m. ttt: initially: Pred.(1.0 mg/ kg/d.) + oral Cph. (50-100
mg/d.), max. 3-4 m.
An alternative: 200 mg/d. Csp alone: (or 100 mg twice d.), max. 3-4 m.. If no resp.
consider R.Tx. Optimal dur. of ttt.
& monitoring is unknown, but:
v Continue ttt.
until A.B. levels become undetectable or no resp.(3-4 m.) .
v Monitor
H.B. weekly to assess for transfusion need & response to therapy.
v Monitor absolute
Retcs & A.B. levels every 1-2 w. dur. ttt. .
v Rechallenge
cn be considered if A.B. levels are below or at lower limit. If performed, start
i.v. EPO.
é (H.B., Retics & A.B. levels)
monitoring.
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