Non EPO Management of Renal Anemia - Different Lines & Available Evidence - Dr. Gawad

Non EPO Management of
Renal Anemia
Different Lines & Available Evidence
Mohammed Abdel Gawad
Nephrology Specialist
Kidney & Urology Center (KUC)
Alexandria – EGY
drgawad@gmail.com
NephroShams: 5-7 Oct 2017

Talk Outline
• Strong evidence: Iron therapy
• Weak evidence: Adjuvant therapies
• 2Ds:
–Dialysis
–Diet
• Emerging therapies:
–HIF (Prolyl-hydroxylase inhibitors)
–Others & Pegnastide

Atkinson MA. Pediatr Nephrol. 2017 Apr 15

This group was on iron
replacement therapy

Hemodial Int. 2017 Jun;21 Suppl 1:S125-S131

CKD 5D CKD ND
IV iron 1–3 month trial of oral
iron therapy
• For CKD ND select the route of iron administration
based on:
– severity of iron deficiency
– availability of venous access
– response to prior oral iron therapy
– side effects with prior oral or IV iron therapy
– patient compliance
– cost

Oral iron supplements
200mg elemental iron / day

Semin Nephrol. 2016 Mar;36(2):130-5

IV iron supplements
Iron Loading

Iron Loading
IV iron supplements

Bailie GR. Kidney Int. 2015 Jan;87(1):162-8
32,435 HD patients
The hospitalization risk was
elevated among patients
receiving ≥ 300mg/month

32,435 HD patients
Bailie GR. Kidney Int. 2015 Jan;87(1):162-8

Iron Markers & Infection in CKD
Serum ferritin & TSAT% are appositive acute
phase reactant and are increased in
inflammatory states and other conditions

Iron Markers in CKD
Bahrainwala J. Semin Nephrol. 2016 Mar;36(2):94-8
Am J Kidney Dis. 2016 Apr;67(4):548-58

Iron Markers in CKD
Bahrainwala J. Semin Nephrol. 2016 Mar;36(2):94-8
The following thresholds are used to diagnose iron
deficiency:
● Percent HRC >6 percent
● CHr <29 pg Am J Kidney Dis. 2016 Apr;67(4):548-58

78 patients undergoing
bone marrow aspirate
was measured to assess
CHr clinical utility for the
diagnosis of iron
deficiency

Any increased risk of infection and cardiovascular
events is believed to be related, at least in part, to
oxidative stress due to iron overload
Iron
& Oxidative stress

There is a shortage of clinical studies to evaluate
whether repeated induction of oxidative stress has
longer-term sequelae in terms of inflammation and
cellular and tissue iron deposition.
Atkinson MA. Pediatr Nephrol. 2017 Apr 15
Iron
& Oxidative stress

This mode of iron delivery provides smaller amounts of
iron over hours compared with supplementation IV,
which may help avoid oxidative toxicity

Seminars in Nephrology. March 2016.
Volume 36, Issue 2, Pages 119–123

Seminars in Nephrology. March 2016.
Volume 36, Issue 2, Pages 119–123
Use Iron once indicated

• Vitamin C • Vitamin D
• Vitamin B12
• Vitamin B6
• Folate
• Vitamin E • L-carnitine
• Pentoxiffylline
• Androgen

Kidney Res Clin Pract. 2012 Mar; 31(1): 48–53
IV ascorbic for 33 patients
500 mg with each dialysis session for 3months
IV ascorbic acid for 20 patients
500 mg once a week for 3 weeks in a month for 3 months + with erythropoietin
6000 IU subcutaneous (S/C) twice weekly, without iron therapy.
J Assoc Physicians India. 2017 Jul;65(7):32-36
+ve results

Kidney Res Clin Pract. 2012 Mar; 31(1): 48–53
IV ascorbic for 33 patients
500 mg with each dialysis session for 3months
IV ascorbic acid for 20 patients
500 mg once a week for 3 weeks in a month for 3 months + with erythropoietin
6000 IU subcutaneous (S/C) twice weekly, without iron therapy.
J Assoc Physicians India. 2017 Jul;65(7):32-36
+ve results
• Number of patients studied
was insufficient to address the
safety of this intervention.
• Thus the long-term safety of
IV ascorbic acid in HD patients
remains undefined, and
whether secondary oxalosis
should be a concern.
But

• Vitamin B12
• Vitamin B6
• Folate
• Pentoxiffylline
• Androgen
+ve results Only if deficient Not studied +ve and –ve
results
Many side
effects

Group A: 38 cases
- serum vitamin D levels (<30 ng/ml)
- vitamin D in a dose of 60000 I.U. orally, once a week
J Assoc Physicians India. 2017 Feb;65(2):38-42.

Locatelli F. Blood Purif. 2017;43(4):338-345

• Vitamin B12
• Vitamin B6
• Folate
• Pentoxiffylline
• Androgen
+ve results Only if deficient Not clear data +ve and –ve
results
Many side
effects

J Nephrol. 2014 Jun;27(3):317-29
Am J Clin Nutr. 2014 Feb;99(2):408-22
Bolignano D. PLoS One. 2015 Aug 3;10(8)
-ve results

Saudi J Kidney Dis Transpl 2017;28(3):477-482
IV 2 g carnitine in every hemodialysis (3 times/week), for 8–10 months
ESA dose
98 patients+ve results

In treatment group, 19 patients received erythropoietin, venofer and
oral pentoxifylline 400 mg/d for 6 months
Erythropoietin-resistant anemia
J Renal Inj Prev. 2016 Nov 26;6(1):61-64
+ve results

• Vitamin B12
• Vitamin B6
• Folate
• Pentoxiffylline
• Androgen
+ve results Only if deficient No clear data +ve and –ve
results
Many side
effects

Clin Nephrol. 1992 May;37(5):264-7
Am J Kidney Dis. 1997 Oct;30(4):495-500
Nephron Clin Pract. 2005;99(4)
+ve results

Clin Nephrol. 1992 May;37(5):264-7
Am J Kidney Dis. 1997 Oct;30(4):495-500
Nephron Clin Pract. 2005;99(4)
+ve results
• All of the 3 RCT are small short-term.
• Currently recommended Hb concentrations were not
achieved.
• In two of them the ESA doses used were lower than
current practice.
• They did not enroll patients with ESA
hyporesponsiveness.

Androgen = Variety of SE
• Acne
• Virilization
• Priapism
• Liver dysfunction
• Injection-site pain (IM)
• Risk for peliosis hepatis
• Hepatocellular carcinoma

Adjuvant Therapy
To Use or Not To Use?
Situation Priority Excluded Caution
ESA
hyporesponsivness
• Vitamin C • Androgen • after exclusion and correction
of all other reversible causes
• Use vit C for short duration
(3months)
RCT for ESA
hyporesponsivness
• Androgen
Evidence of
deficiency
Other indication
than treating
anemia
Self opinion
Use adjuvant therapy in one of the following situations:
M. Abdel Gawad. Nephro-Shams, 7 Oct, 2017

Nephrol Dial Transplant. 2001 Jan;16(1):111-4

J Nephrol. 2003 Jul-Aug;16(4):546-51

ESA dose
No significant difference between the groups
at any follow-up time.
Ornt DB. Nephrol Dial Transplant. 2013 Jul;28(7):1888-98

Hb Level
Hb concentrations increased significantly in
the 6× versus 3× group, but both groups had
Hb concentrations in the usual target range.

More frequent HD did not have a significant
or clinically important effect on anemia
management.
Hb Level
Hb concentrations increased significantly in
the 6× versus 3× group, but both groups had
Hb concentrations in the usual target range.

Susantitaphong P. Nephrol Dial Transplant.
2013 Feb;28(2):438-46

Georgatzakou HT. Can J Physiol Pharmacol. 2017 Aug 30

phosphatidylserine

phosphatidylserine
The nature of these adverse short-term effects
of HDF on post-dialysis plasma and RBCs
strongly suggests the use of a parallel
antioxidant therapy during the HDF session

Nephrol Dial
Transplant. 2013 Jul;
28(7): 1936–1945

Dietary Management
Sources of heme iron Sources of non-heme iron
Lean meat
Red meat
Sea food
Nuts
Beans
Vegetables fortified grain products
• Milk and milk products, tannins and caffeine inhibit iron
absorption and should be avoided with iron rich sources of food.
• Vitamin C can improve iron absorption and can be administered
concomitantly with iron rich foods.

Francesco Locatelli. Am J Nephrol. 2017;45(3):187-199
HIF – Stabilizers: Main Idea
EPO Dependent Effect

Nupur Gupta. Am J Kidney Dis. 2017;69(6):815-826
HIF – Stabilizers:
Main Idea
EPO Dependent
Effect

Francesco Locatelli. Am J Nephrol. 2017;45(3):187-199
Prolyl-hydroxylase
HIF Stabilizers
=
Prolyl-hydroxylase
inhibitors

Koury MJ. Nat Rev Nephrol. 2015 Jul;11(7):394-410

HIF – Stabilizers: Iron metabolism
Koury MJ. Nat Rev Nephrol. 2015 Jul;11(7):394-410

Nupur Gupta. Am J Kidney Dis. 2017;69(6):815-826
HIF –
Stabilizers:
Iron
metabolism

HIF – Stabilizers: Hepcidin
HIF – Stabilizers cause reduction in serum
hepcidin levels.
It is still unknown whether this is a direct or
indirect effect related to HIF stabilization
Mario Bonomini. Am J Kidney Dis. 2016;67(1):133-142

Advantages of HIF-Stabilizers over ESA
• Orally administered
• Induce physiologic EPO levels
• Increase iron

Nat Rev Nephrol. 2016 Mar;12(3):157-68

Mario Bonomini. Am J Kidney Dis.
2016;67(1):133-142
López-Gómez JM. Nefrologia.
2016 May-Jun;36(3):232-6
van Eijk LT. Blood.
2014 Oct 23;124(17):2643-6

N Engl J Med 2013;368:320-32
N Engl J Med 2013;368:307-19.

Home Messages
Iron
• Iron is a cornerstone in management of renal
anemia
• Alternate iron assessment markers can be
used if infection is suspicious

Home Messages
Adjuvant Therapies
Situation Priority Excluded Caution
ESA
hyporesponsivness
• Vitamin C • Androgen • after exclusion and correction
of all other reversible causes
• Use vit C for short duration
(3months)
RCT for ESA
hyporesponsivness
• Androgen
Evidence of
deficiency
Other indication
than treating
anemia

Home Messages
Dialysis
• Higher dialysis adequacy (within limits) = better
ESA response
• No benefit for daily and nocturnal dialysis
regarding enhancing ESA response
• Ultrapure dialysate = better ESA response
• HDF induces acute oxidant effect

Home Messages
• Diet is a corner of anemia management
• Emergent therapies are available, the most
promising is HIF

Non EPO Management of Renal Anemia - Different Lines & Available Evidence - Dr. Gawad

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