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Anémie chez le patient transplanté rénal

Gabriel ChoukrounNephrology – Internal Medicine – Dialysis –Transplantation Department

MP3CV Research UnitAmiens

Liens d’intérêts

• Astellas• Astra Zeneca• Genzyme – Sanofi• GSK• Takeda• Vifor Renal Pharma

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o Prévalenceo Mécanismes et causes possibleso Retentissement et bénéfices du traitemento Recommandations de prise en charge

L’anémie du patient transplanté rénal

Adapted from MZ Molnar et al., Nephron Clin Pract 2011

n = 5 834 - 10 centers, 4 countries in EuropeDefinition of anemia: Hb < 13 g/dl in M and < 12 g/dl in F

Post-transplant anemia remains a frequent condition

Cross-sectional study

Time since Tx Whole population(n = 5 834)

< 6 months(n = 56)

1 - 3 years(n = 913)

3 - 5 years(n = 893)

> 5 years(n = 3 726)

Age (yrs) 50 ± 14 45 ± 13 47 ± 14 48 ± 14 51 ± 14

Hb (g/dl) 12.9 ± 17.0 12.0 ± 18.0 12.9 ± 17.0 13.0 ± 17.0 12.8 ± 17.0

eGFR (ml/min) 47 ± 19 50 ± 20 51 ± 19 48 ± 19 46 ± 20

Anemia (%) 42 59 42 36 44

Hb < 11 g/dl) 14 29 14 12 14

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MZ Molnar et al., Nephron Clin Pract 2011; SI McFarlane et al., Am J Kidney Dis 2008

For the same level of GFR, anemia is more prevalent in transplant patients

Definition of anemia: Hb < 13 g/dl in M and < 12 g/dl in F

Transplantation CKD

30 – 50 % au stade 3 MRC

ShortenedRBC survival

Redblood cells

HaemoglobinProtein in red blood cells responsible for oxygen

transport

Iron Major building block of

RBC production

Irontransport

Hepcidin Reduces availability of

iron for RBC production

Liver GutMacrophage

Adapted from: Ganz T et al., Hematology Am Soc Hematol Educ Program 2011; Goodnough L. Transfusion 2012; Malyszko J et al., Kidney Blood Press Res 2007; Weiss G et al., N Engl J Med 2005

InflammationIncreases hepcidin levels

IFN- IL-6

Bone marrow Site of red blood cell precursors and their

EPO receptors

Liver Kidney

Erythropoietin

Uremic inhibitors

Factors involved in CKD anemia

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Erythropoietin production after kidney transplantation

Adapted from CH Sun et al., New Engl J Med 1989

PTA at 3 months PTA after 6 months

Low pre-Tx Hb and surgery +++Delayed graft function +++ +Donor age and Recipient sex + +Infection and Inflammation ++ ++

Chronic Allograft Nephropathy ++++

MAT, Lymphoma, cancer ++ ++ACEI or ARB + ++

MMF, azathioprine, Sirolimus ++ ++

Vitamins and Iron deficiency +++ +++

Factors associated with post-transplant anemia (PTA)

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n = 464r = 0.298 - p < 0.01

40

60

80

100

120

140

160

180

0 10 20 30 40 50 60 70 80 90 100 110 120 130

eGFR - MDRD (ml/min)

Hb

(g/l)

Hemoglobin level is « well » correlate to renal function

G Choukroun et al. for the MATRIX study, Nephrol Therap 2006

Complete blood count, which include Hb concentration, red cell indices, white blood cell count and differential and platelet count

Absolute reticulocyte count Serum ferritin level Serum transferrin saturation (TSAT) Serum vitamin B12 and folate levels

In patients with CKD and anemia, include the following tests in initial evaluation of anemia

How to explore an anaemia in CKD

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Inflammation blocks iron utilisation in CKD patients

G Weiss et al., N Engl J Med; LT Goodnough, Transfusion 2012; B Young et al., Clin J Am Soc Nephrol 2009

Inflammation

IL-6

Intestinal absorptive cells(enterocytes)

Reticuloendothelial macrophage(Liver and spleen)

Hepcidin

Hepcidin Hepcidin

Inhibition of iron release from enterocytes into

the circulation

Reduction of ironrelease from macrophages

Dietary iron is not absorbed orreleased into circulation

Iron is trapped instorage cells

• Chronic inflammation• Infections• IV iron therapy• Reduced renal clearance of hepcidin

o Asthénie et perte d’appétito Diminution des performances physiques à l’efforto Augmentation du risque infectieux o Augmentation de la fréquence des hospitalisationso « Altération » de la qualité de vie

Principales conséquences de l’anémieQuel niveau d’Hb optimal ?

Hb cible (g/dl)

8

12

14

16

10

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Anemia in CKD: a risk amplifier for adverse outcomes

Anemia in CKD is associated with an increased risk for coronary heart disease,increased risk of stroke, mortality and progression to ESKD

Jurkovitz C et al. J Am Soc Nephrol 2003; Horwich TB et al. J Am Coll Cardiol 2002; Abramson JL et al. Kidney Int 2003;Kovesdy CP et al. Kidney Int 2006; Kazory A, Ross EA. Am Coll Cardiol 2009; Johnson E et al. Am J Kidney Dis 2007

Risk of stroke

Risk of CHD

Mortality

Progression to ESKD

x 5.43

x 2.74

x 2.96

x 2.10

Fold increase of CHD events

Fold increase of events

Fold increase of events

CKD

Anemia

D. Chhabra et al., ATC 2007

Survie du patient

25

40

55

70

85

100

3 18 33 48 63 78 93 108 Mois post-Tx

Hg > 11g/dlHg < 11g/dl

HR : 3,2IC95 : 1,78-5,73p < 0,0001

25

40

55

70

85

100

3 18 33 48 63 78 93 108 Mois post-Tx

Hg ≥ 11g/dlHg < 11g/dl

HR : 2,74IC95 : 1,93-3,91p < 0,0001

Survie du greffon

Données ajustées pour l’âge du donneur, le sexe et l’ethnie du receveur, l’Hb pré-Tx, l’utilisation du MMF et des stéroïdes et le DFG estimé

Événements observés pendant la période de suivi 89 décès (9 %) 235 pertes de greffon (23 %)143 épisodes de rejet aigu (14%)

Étude rétrospective (n = 1 023) [Tx entre 1992 et 2003] - Suivi médian : 4 ans (0,2 - 12,6 ans)Définition de l’anémie : Hb moyenne à 3 mois < 110 g/l

Impact de l’anémie post-Tx sur la survie du patient et du greffon

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Impact de l’anémie post-Tx sur la survie du patient et du greffon

A Gafter-Gvili et al., Medicine 2017Rétrospective sur 4 ans (2008 – 2011) – Follow-up time 5.46 ± 1.21 ans (n = 261)

Quel bénéfice du traitement de l’anémie ?

IV iron

ESA therapy

Blood transfusion

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Hb

(g/d

l)

4

6

8

10

12

14

16

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42

2

0

Time post-Tx (weeks)

Evolution of hemoglobin after renal transplantationIs there a benefit of anemia treatment ?

Martinez et al(n = 104)

Aydin et al(n = 92)

Hafer et al(n = 88)

Sureshkumar et al.(n = 72)

Study Multicentric, open vscontrol

Monocentric, double blind vs placebo

Monocentric, double blind vs placebo

Monocentric, double blind vs placebo

Patients Risk of DGF Non beating heart donors Decease donors Decease donors

Dose ASE 4 x 30 000 UI(IV – SC)

3 x 33 000 UI(IV)

3 x 40 000 UI(IA – IV)

40 000 UI x 1(IA)

Objectives Renal function 1 months and DGF

Renal function 1 week and DGF

Renal function 6 weeks and DGF

Renal function at 1 w and DGF

Results No difference No difference No difference No difference

Secondary Hb increase Better eGFR at 1 yr No difference No difference

Safety No Thrombosis No No

There is no benefits of the use of ESA during the first weeks following renal transplantation on kidney function

F Martinez et al., Am J Transplantation 2010; Z Aydin et al., Am J Transplantation 2012; C Hafer et al., Kidney Int 2011;KK Sureshkumar et al., Clin J Am Soc Nephrol 2012

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Neo-PDGF StudyRenal function: eGFR (MDRD)

D21 D30 D60 D90D14D7B

60

50

40

30

20

10

0

eGFR

(ml/m

in) Group A Epoetin beta

Group B Control

Time after randomization (days)

F Martinez et al., Am J Transplant 2010

Neo-PDGF StudyESA is effective to correct anemia during the first weeks following renal transplantation

D21 D30 D60 D90D14D7B

14

13

12

11

10

9

8

Seru

m H

emog

lobi

n le

vel (

g/dl

)

* p < 0.02

Group A Epoetin beta

Group B Control

Time after randomization (days)

Group Epoetin

Control

Pts with Hb > 12 g/dl at d-30

15 (31.9 %) 5 (10.2 %)

F Martinez et al., Am J Transplant 2010

Epoetin beta (30 000 UI x 4) IV then SC

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Investigate the effect of suboptimal anemia correction in kidney transplant recipients with chronic allograft nephropathy (stage 3 to 4 CKD) and anemia on the rate of progression of kidney

dysfunction, quality of life, and left ventricular remodeling

Tx > 12 monthseClcr 50 - 20 ml/minHb < 115 g/Ln = 125

R

Group A : Hb 130 - 150 g/L

Group B : Hb 105 - 115 g/L

QoL QoL QoLeGFR eGFR eGFR eGFR eGFR

Epoetin beta SC

Goals and design of the study

Renal function at inclusion

Follow-up

150

140

110

100

90

80

120

70

130

Hem

oglo

bin

(g/l)

T0 M1 M6 M12M2 M24

Evolution of serum Hb level during the study

M3 M9 M18

59.0 %37.7 %

55.0 %36.2 %

54.5 %39.1 %Iron treatment A

B

Blood transfusion 1 (1.6 %) in A, and 5 (8.1 %) in B

89 %5600 ± 2700 UI/s

94 %6100 ± 3600 UI/s

92 %6500 ± 4400 UI/s

61 %4600 ± 3600 UI/s

41 %3600 ± 2100 UI/s

64 %4600 ± 3800 UI/s

G Choukroun et al., J Am Soc Nephrol 2012

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G Choukroun et al., J Am Soc Nephrol 2012

Renal function at inclusionQuality of Life at 1 yearSF-36 Questionnaire

40

30

0

- 10

10

20

RPPF BP GH VT RESF MH

50 Group A (130 - 150 g/l)Group B (105 - 115 g/l)

* p < 0.05

*

* *

*

*

*

Physical General Health Social, Emotional, Mental

Vari

atio

n fr

om b

asel

ine

(%)

B M6 M12 M24M-2M-4M-6

50

45

40

35

30

0

eGFR

(ml/m

in)

Group A Hb 13 – 15 g/dl

Group B 10.5 – 11.5 g/dl

Time after randomization

Renal functioneGFR (MDRD)

*

p < 0.025

A n 63 61 60 58B n 62 61 58 59

M9

*

G Choukroun et al., J Am Soc Nephrol 2012

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Graft survivalKaplan-Meier analysis: death-censored graft survival

Group A (13.0 – 15.0 g/dl)

Group B (10.5 – 11.5 g/dl)

Cum

ulat

ive

graf

t sur

viva

l (%

)

Time to ESRD (months)

100

80

60

4

40

0

20

08 12 16 20 24

p < 0.01

Group A130 - 150 g/L

Group B105 - 115 g/L

Scr x 2 (n) 2 10 *

BPAR (n) 0 0

ESRD (n, %) 3 (4.8 %) 13 (21.0 %) *

Duration before ESRD (months) 17.8 ± 1.2 15.4 ± 5.5

G Choukroun et al., J Am Soc Nephrol 2012

High hemoglobin level and long-term kidney functionA Japanese randomized controlled trial

M Tsujita et al., Nephrol Dial Transplant 2018

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M Tsujita et al., Nephrol Dial Transplant 2018

High hemoglobin level and long-term kidney functionA Japanese randomized controlled trial

Potential mechanisms for nephroprotection

o Epithelial tubular cells hypoxia increases interstitial fibrosiso Hypoxia stimulates production of extracellular matrix and synthesis of profibrosis cytokines

(TGF-,…)o Erythrocytes are important antioxidant component of plasmao EPO activates erythropoiesis and reduces tissue hypoxiao EPO reduces oxidative stress and production of ROSo EPO has antiapoptotic action on erythrocytes, neurons, epithelial, and endothelial cells

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Epoetin protects from chronic allograft nephropathyExperimental data

P Cassis et al., Kidney Int 2012

Epoetin Erythropoïétines recombinantes modifiées Peptides stimulants l’érythropoïèse pégylés Inhibiteurs de la prolyl hydroxylase

Utilisation des ASE pour traiter l’anémie dans l’IRC

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KDIGOConduite du traitement

KDIGO 2012, Kidney Int 2012

Maintenir le taux d’Hb entre 10 et 11.5 g/dl chez une majorité de patients (10 et12 g/dl pour les EBPG 2013)

Ne pas dépasser 13.0 g/dl intentionnellement

Lorsqu’une baisse du taux d’Hb est nécessaire, privilégier une réduction de doseplutôt qu’un arrêt temporaire du traitement

Il n’y a pas de bénéfice, en dehors de l’amélioration de la qualité de vie, à cibler un taux d’Hb > 13 g/dl, quelque soit le stade de la MRC

GuidelinesRecommendation on the use of iron (IV or oral)

KDIGO Work Group. Kidney Int Suppl 2012; EBPG, Nephrol Dial Transplant 2013

2.1.2. For adult CKD patients with anaemia not on iron or ESA therapy, we suggest a trial of IV iron (or in CKD ND patients alternatively a 1- to 3-month trial of oral iron therapy)

2.1.3. For adult CKD patients on ESA therapy who are not receiving iron supplementation, we suggest a trial of IV iron (or in CKD ND patients alternatively a 1- to 3-month trial of oral iron therapy)

Use of iron to treat anemia in CKDGuidelines recommend iron treatment if:An increase in Hb concentration without starting ESA is desired, and TSAT ≤ 30% or SF ≤ 500 ng/mL (K-DIGO) or TSAT ≤ 25% or SF ≤ 200 ng/mL (300 if stage 5) (ERBP)

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What are the thresholds for the treatment of Iron Deficient Anemia?

Absolute iron deficiency : SF < 100 µg/L and TSAT < 20 %

Kidney disease: Improving Global Outcomes (KDIGO) Work Group. Kidney Int Suppl 2012; Locatelli F et al. ERBP Guidelines. Nephrol Dial Transplant 2013; NICE Guideline NG8. Chronic kidney disease: managing anaemia 2015

KDIGO ERBP NICE

Iron deficiency(ESA-naïve)

SF ≤ 500 μg/L andTSAT ≤ 30%

SF < 200 μg/L andTSAT < 25%

For IDA: SF <100 μg/L and TSAT <20%

SF is recommended for assessment of iron overload; SF levels should not rise above 800 μg/L

Iron deficiency(on ESA therapy)

SF ≤ 500 μg/L andTSAT ≤ 30%

SF < 300 μg/L andTSAT < 30%

KDIGOInstauration du traitement par ASE

Chez les patients non dialysés ayant un taux d’Hb < 10 g/dl

Si l’anémie est symptomatique En fonction de la vitesse de décroissance du taux d’Hb Pour éviter la transfusion sanguine

KDIGO 2012, Kidney Int 2012

Chez les patients dialysés si le taux d’Hb est entre 9 et 10 g/dl

Individualisation

Instauration du traitement possible si Hb ≥ 10 g/dl

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o Mechanisms responsible for anemia in CKD patients and after transplantation aredifferent

o The use of high dose of ESA during the first hours following kidney transplantationhad no effect on renal function recovery

o Whereas in CKD patients, targeting a Hb value of 13 g/dl or above had no effect insurvival and in the rate of progression of renal failure, in kidney transplant recipientswith allograft nephropathy, a Hb target of 13 – 15 g/dl is associated with a decrease inthe progression of renal failure, a better graft survival and an improvement of Qualityof Life

Conclusion