anemia in ckd - university...
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ANEMIA IN CKD Anna Vinnikova, MD
Causes of anemia in CKD
• EPO deficiency
• Hepcidin excess
• Iron deficiency
• Shortened RBC survival
• Bleeding
• HPT
• Any other cause of anemia
Iron homeostasis
Iron homeostasis
Absorption
Excretion
Recycling
Absorption
Absorption
Iron
Ferritin
Ferritin
Transferrin,TIBC
Transferrin saturation
Ferroportin
Hepcidin
Absorption
Recycling
Recycling
Storage
Tissue ferritin
Serum ferritin
Regulation
Hepcidin
Professional iron exporters
• Enterocytes
• Macrophages
• Hepatocytes
hepcidin
• Low iron
• EPO
Low hepcidin
hepcidin
• Inflammation
Hepcidin also accumulates in renal failure
Hepcidin excess
The ESA saga
Anemia in CKD is associated with:
symptoms
increased risk of hospitalization and
death
increased CV m&m
Anemia in CKD presents high transfusion
requirement
Partial correction of anemia improves QOL
• Anemia in CKD directly causes increased rate of
hospitalization, death and CV events
• Treatment of anemia in CKD will improve CV m&m
1989 EPO approved by FDA
Presciousbodyfluids.com
2004
• K/DOQI recommend Hgb goals 11-14 based on
observational evidence
Presciousbodyfluids.com
Presciousbodyfluids.com
1998 “Normal Hematocrit Study”
• Ramdomized 1200 patients on HD to be treated w EPO
• Target Hct 30
• Target Hct 42
• Endpoint – time to death or MI
• Observation 30 mo
• Study terminated early due to increase in CV
endpoints (RR1.3) and access thrombosis in normal
Hct group
2006 CHOIR, NEJM
• US study
• Ramdomized 1400 patients w CKD to be treated w EPO
• Hgb 11.5
• Hgb 13.5
• Composite CV endpoints (time to death, MI, CHF, CVA)
• Observation: 16 mo
• Study terminated early sec to futility and slightly
increased CV risk in high Hgb target group
2008, secondary analysis of CHOIR, NEJM
• Showed that not all patients in the high Hgb target group
were at increased CV risk
• The subgroup who could not achieve the target and
therefore received high EPO doses were at increased risk
CREATE, 11/2006, NEJM
• European study
• Randomized 600 patients w CKD to be treated w EPO
• Hgb 10.5-11.5
• Hgb 13-15
• Composite CV endpoints (time to first CV event)
• Observation: 3 yrs
• Results:
• High Hgb group:
+ increased QoL
- shorter time to dialysis
- CV risk same between groups
2007
• K/DOQI anemia update
• Use ESA to target Hgb 11-12, keep <13
TREAT, 11/2009, NEJM
• Study randomized 4,000 patients with DM and CKD
• DPO to Hgb >13
• No DPO (allowed DPO rescue for Hgb <9)
• Endpoint: death or CV event
• Observation 29 mo
• Result: DPO group less CABG but more CVA, o/w no
difference
2011
• FDA ESA black box warning:
• Start ESA for Hgb <10; but
• Hgb >11 increases CV risk
Novel anemia therapies
Novel anemia therapies
• Exogenous
• rhEPO
• EPO-mimetics
• Endogenous
• GATA-2-inhibitors
• HIF-stabilizers
• Hepcidin inhibitors
Iron deficiency in CKD/ESRD patients
• Absolute iron deficiency in CKD:
• T sat <20%
• Ferritin <200 (<100 in CKD)
• Functional iron deficiency in CKD:
• T sat <20% and Ferritin >200
• Inflammatory block
• T sat <20% and Ferritin >200 who fail to respond to IV iron
DRIVE 2007
• 134 HD patients w Hgb <11, Tsat <25% and ferritin 500-
1200, on high EPO doses
• Randomized to 25% EPO dose increase+/- Ferrlecid load
• Patients on Ferrlecid responded better w less EPO, AE
identical
Ferrous fumarate — 106 mg elemental iron/tab
Ferrous sulfate — 65 mg elemental iron/tab
Ferrous gluconate — 28 to 36 mg iron/tab
Feraheme