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

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