Updates on Anemia Management in Patients with

CKD

Masaomi Nangaku Division of Nephrology and Endocrinology

the University of Tokyo Graduate School of Medicine

High Hb in patients treated with darbepoetin alfa is associated

with better prognosis: a post-marketing surveillance in Japan

Tanaka, Nangaku et al. Clin Exp Nephrol 2019

Composite renal endpoints: 50% reduction

in eGFR, initiation of dialysis, or kidney

transplantation

Hb level at 3 months of treatment: < 11g/dL

Hb level at 3 months of treatment: ≥ 11g/dL

p < 0.0001 (Log-rank test) Cu

mu

lati

ve p

rop

ort

ion

s

of

ren

al su

rviv

al

N=5,024

Hirakawa, Nangaku, et al. J Diabetes Investig 2017

Cellular responses against anemia and hypoxia

Oxygen transport (EPO, Transferrin)

Vascular regulation (VEGF, adrenomedullin, HO-1)

Glucose uptake and glycolysis (Glut-1, Aldolase A)

Anti-oxidative enzymes (SODs, catalase)

Sugahara, Tanaka T, Nangaku. Kidney Int 2017

HIF activation as novel

treatment of anemia in

CKD

liver

spleen duodenum

Bone

marrow

hepcidin

HIF activator improves anemia in CKD

Akizawa, Nangaku et al.

Am J Nephrol 2017

daprodustat in Japanese HD patients

phase 2 phase 3

Akizawa, Nangaku et al.

Ther Apher Dial 2019

Akizawa, Nangaku et al.

Am J Nephrol 2019

enarodustat in Japanese HD patients

enarodustat in Japanese

non-HD patients

Akizawa, Nangaku et al.

Nephron 2019

HIF activator improves anemia in CKD

Placebo

Daprodustat 4 mg 6 mg 8 mg 10 mg

Total Chol (mmol/L)

Baseline 95% CI

3.8 (3.5, 4.2)

4.0 (3.7, 4.5)

3.9 (3.6, 4.4)

3.7 (3.3, 4.2)

3.9 (3.6, 4.2)

Week 4 CFB 95% CI

5.3 (-0.6, 11.6)

-7.4 (-12.2, -2.3)

-10.8 (-15.3, -6.0)

-9.0 (-14.9, -2.7)

-14.6 (-19.8, -9.0)

LDL-C (mmol/L)

Baseline 95% CI

2.0 (1.7, 2.3)

2.2 (1.9, 2.5)

2.1 (1.8, 2.4)

1.9 (1.6, 2.3)

2.1 (1.8, 2.4)

Week 4 CFB 95% CI

4.8 (-10.4, 22.5)

-11.1 (-17.2, -4.7)

-10.8 (-17.2, -4.0)

-12.5 (-18.8, -5.7)

-17.3 (-24.3, -9.6)

Akizawa, Nangaku et al. Am J Nephrol 2017

decreases in the lipid parameters by daprodustat

HIF activation improved obesity and

fatty liver in mice fed with high fat diet

0

10

20

30

40

50

60

0 4 8 12 16 20

BW

(G)

WEEKS

BODY WEIGHT (G)

HFD HFD+JTZ-951 ND

HFD HFD+JTZ-951 ND

0

0.5

1

1.5

2

2.5

3

3.5

4

sco

re o

f h

ep

ati

c

ste

ato

sis

hepatic steatosis

Saito, Nangaku et al. Lab Invest 2019

Akizawa, Nangaku et al. Am J Nephrol 2019

Changes of iron status: enarodustat

ferritin TIBC

TSAT hepcidin

phase 3 study in Japanese HD patients

Akizawa, Nangaku et al. Ther Apher Dial 2019

Changes of iron status: daprodustat

TSAT ferritin

hepcidin TIBC

first case of doping with HIF activator, FG-4592

Buisson et al. J Pharm Biomed Anal 2016

Fukui, Nangaku et al. Eur J Pharmacol 2019

Effects of enarodustat on VEGF production

plasma retina

Figure 3 HIF-1ɑ promotes cyst progression in a mouse model

of ADPKD

HIF-1ɑ promotes cyst growth in PKD, presumably through

calcium-activated chloride secretion Kraus et al. Kidney Int 2018

Hypoxia as the final common pathway to End

Stage Kidney Disease

Nangaku. J Am Soc Nephrol 2006

Mint3 reduces fibrosis of hypoxic kidney through

protection of tubular epithelial cells from apoptosis

Nasu, Nangaku et al. Nephrol Dial Transplant in press

HIF activation improves AKI

0

1

2

3

4

5

6

0 1 2 3 4

PAS score

S.C

r (

mg/

dl )

Control

Cobalt

r2=0.833

P<0.001 Control

Treatment

Positive correlation between

creatinine and tubular injury

PAS staining

Matsumoto, Nangaku et al. J Am Soc Nephrol 2003

Nordquist, Nangaku et al. J Am Soc Nephrol 2014

HIF activation improves DKD

Renoprotection by HIF activator by anti-inflammatory

response in a model of tubulointerstitial nephritis

Schley et al. Kidney Int 2019

Chen et al. N Engl J Med 2019

Chen et al. N Engl J Med 2019

The primary end point:

The mean change in hemoglobin

level from baseline to the average

level during weeks 23 through 27

Average age of Japanese HD

patients is 68.4

Average duration of Japanese HD patients is 7.3

Patients with duration over 10 years are 27.8% and over 20 years are 8.3%, respectively

Representativeness of RCT cohorts in ESKD

Smyth et al. JAMA Intern Med 2019

meta-analysis of 189 RCTs

enrolling 80,104 participants

comparison with USRDS

population

RCT participants were younger

and less likely to have diabetes.

The mortality rate during trial

participation was less than half

that of the USRDS population.

Chen et al. N Engl J Med 2019

Roxadustat

(N=204)

Epoetin alpha

(N=100)

Hemoglobin

Chen et al. N Engl J Med 2019

Hepcidin

Chen et al. N Engl J Med 2019

Chen et al. N Engl J Med 2019

Chen et al. N Engl J Med 2019

Placebo

Roxadusutat

Hemoglobin

Chen et al. N Engl J Med 2019

Roxadustat Placebo Between group difference

95% CI

Total Chol -40.6 mg/dL -7.7 mg/dL -0.9 mmol/L -1.1 to -0.6 mmol/L

LDL-Chol -25.3 mg/dL - 5.8 mg/dL -0.5 mmol/L -0.8 to -0.3 mmol/L

Changes of lipid parameters at 9 week

Chen et al. N Engl J Med 2019

Chaired by Kai-Uwe Eckardt & Jeff Berns

19-21 June

2020