Erythropoietin Resistance from Failed Renal Allograft: Case Report - PowerPoint Presentation

Slide1

Erythropoietin Resistance from Failed Renal Allograft: Case Report

Can Huzmeli

Necip Fazıl

City

Hospital

Kahramanmaras

/

Turkey

Slide2

Anemia is one of the most important complications of chronic kidney disease.

Erythropoietin

deficiency is

one

of

the most common cause of anemia in patients with chronic kidney disease.

Slide3

Erythropoietin Resistance

According to the

Kidney Disease Outcomes Quality Initiative

Guideline

erythropoietin

resistance;

d

espite

regular and full dose

erythropoietin

treatment, it is defined as a significant decrease in

hemoglobin

levels or a significant increase in

erythropoietin

dose required to maintain a certain level of

hemoglobin

or a failure to reach 11 g /

dL

hemoglobin

levels despite the administration of 500 U / kg / week

epoetin

or equivalent dose

of

erythropoietin

.

National Kidney Foundation. K/DOQI Clinical Practice Guidelines

and Clinical Practice

R

ecommendations

for Anemia in Chronic

Kidney Disease. Am J Kidney

Dis

2006;47:1-145

Slide4

Erythropoietin Resistance

The

European

Best

Practice

Guideline

defines

erythropoietin

resistance

as

requiring

>20.000 IU (> 300 IU / kg)

erythropoietin

alpha

or

beta

or

1.5

μ

g / kg of

darbepoetin

alfa

(> 100

μ

g /

week

)

per

week

.

Locatelli

F, et al.

European

Best Practice Guidelines Working G: Revised European best practice

guidelines for the management of

anaemia

in patients with chronic

renal

failure

.

Nephrol

Dial

Transplant

, 19(

Suppl

. 2):ii1–ii47, 2004

Slide5

Risk F

actors for

E

rythropoietin

R

esistance

Absolute or functional iron deficiency

Gastrointestinal

blood

loss

Hemolysis

Inflammation

infection

Malignancy

Folic

acid

deficiency

Alves

MT et al.

Resistance of dialyzed patients to

erytropoietin

. Rev

Bras

Hematol

Hemoter

2015

Slide6

Risk

F

actors for

E

rythropoietin

R

esistance

Vitamin B12

deficiency

,

Insufficient

hemodialysis

Hyperparathyroidism

Angiotensin

converting

enzyme

inhibitor

Angiotensin

II

receptor

blocker

Anti-

erythropoietin

antibody

Alves

MT

et al.

Resistance of dialyzed patients to

erytropoietin

. Rev

Bras

Hematol

Hemoter

2015

Slide7

Case

52

year

old

male

In May 2005, idiopathic chronic renal disease stage 5 was included in the

hemodialysis

program for 3 days per week

In September 2012, the kidney transplant

(

deceased

donor

)

was made to the patient

Hemodialysis

started again in February 2015 with renal graft failure

Slide8

Case

He was using

cyclosporin

and

methylprednisolone

Immunosuppressive medication was discontinued 3 months after starting

hemodialysis

A

total of 5 times

replacement

of

erythrocyte suspension

(2U

each

time)

was made

to

the

patient

Slide9

Semptoms

Fever

weakness

Fatigue

Sensitivity in the graft region

Slide10

Laboratory

Before

treatment

After

treatment

Hemoglobin (gr/

dL

)

5.4

13

Blood urea nitrogen mg / dL

46

50

Serum

creatinine

(mg/

dL

)

7.8

6.5

Total

protein

(

gr / d

L)

6,5

7.2

Albumin

(

gr /

dL

)

2.2

3.2

Ferritin

(

ng

/mL)

> 2000

1327

Transferrin

saturation

40%

30

C-reactive protein

(mg/L)

117

13

Sedimentation

(mm /

hour

)

70

35

URR

73%

70%

Kt

/v

1.34

1.30

Slide11

Hematuria

was present in urine

analysis

.

Renal

ultrasonography

was

interpreted as

normal

.

P

eripheral

blood

smear

was consistent with

normocytic

normochromic

anemia

.

Bone marrow biopsy was normal.

Culture of blood, urine

and

sputum consistently

was

negative

.

CMV

IgM

test was

negative

.

Slide12

The patient was

us

ing

epoetin

beta 150 U / kg and vitamin D in

treatment

.

With the diagnosis of

G

raft

I

ntolerance

S

yndrome

, 10 mg of

methylprednisolone

was

given

.

Erythropoietin treatment was discontinued after 4 months of treatment with

methylprednisolone

on

Hb

11.8

gr

/

dl

.

Methylprednisolone

therapy was discontinued after 6 months

.

Anemia

did not occur

in

the

patient

even though passed

one

year

.

Slide13

*

US data suggest that patients with failed transplants constitute 4.1% of the incident dialysis population and are now the fifth commonest cause of starting dialysis in the

US

.

*

In the UK, between 2011 and 2012, 27% of those who die of kidney transplantation have experienced graft failure before dying.

Slide14

Distribution of

Renal

transplantation

patients with functioning graft according to donor source as of the end of 2015 (according to the data obtained from 18 centers

Living

donor

5111

Deceased

donor

1404

Total

6515

Slide15

Distribution of all renal

transplantation

patients transplanted in 2015 according to final situation as of the end of 2015

in

Turkey

Followed

with

functioning graft

3068 (%95,7)

Returned

to

dialysis

42 (%1,31)

Died

94 (%2,93)

Total

3204

Living

donor

2534

Returned

to

dialysis

in

living

donor

28

Death

in

living

donor

43

Deceased

donor

670

Returned

to

dialysis

in

deceased

donor

14

Death

in

deceased

donor

51

Slide16

Mortality

for transplant failure patients on dialysis

was

twice as high compared

with the risk for transplant-naive patients

.

All-cause mortality

was

32% higher for transplant failure patients on dialysis than for transplant-naive patients

.

Mortality rates were

lowest

in patients with good graft function, high in waiting list, and highest in patients returning to dialysis as a result of developing graft

failure

.

Gill JS,

et al.

The importance of transition

between dialysis and transplantation in the case of end-stage renal

disease patients. Kidney

Int

2007;71:442-447

Fernandez

Fresnedo

G et al.

Survival

after

dialysis

initiation: a comparison of transplant patients after graft loss versus

nontransplant

patients. Transplant Proc 2008; 40: 2889–2890

.

Perl J

,

et al.

Reduced survival and quality of life following

return to dialysis after transplant failure: the Dialysis Outcomes and

Practice Patterns Study.

Nephrol

Dial Transplant 2012; 27: 4464–4472

Slide17

Anemia

was

associated with increased risk of mortality in patients who have lost grafts.

Patients who have lost the graft and have returned to dialysis have been shown to be more anemic due to erythropoietin resistance than patients on

dialysis

.

Solid

CA,

Epoetin

use and kidney disease outcomes quality initiative hemoglobin

targets in patients returning to dialysis with failed renal transplants.

Kidney

Int

2007

Slide18

Continuation of immunosuppression after a failed transplant

Potential

beneficial

effects

Preservation of residual kidney function

Decreased incidence of graft intolerance syndrome and the need for

allograft

nephrectomy

Minimization

of

allosensitization

Avoidance of overt acute rejection

Prevention of adrenal insufficiency syndrome

Prevention of reactivation of systemic disease (

e.g., systemic lupus

erythematosus

,

vasculitis

)

Potential

adverse

effects

Metabolic

complications (

diabetes

, hypertension,

dyslipidemia

)Steroid-associated adverse effects (e.g., diabetes, cataracts, myopathy, andavascular necrosis among others)Cardiovascular complicationsIncreased susceptibility to infectionMalignancy (especially skin cancers, Kaposi’s sarcoma, non-Hodgkin’slymphoma, and lip cancers)Costs (particularly when data supporting continued immunosuppressionare lacking)

Pham P

T

et al.

Management of patients with

a failed kidney transplant: Dialysis 

reinitiation

, 

immunosuppressionweaning

, and 

transplantectomy

.

World

Nephrol

.

 2015

Slide19

Reasons for

Withdrawal

of

Immunosuppression

After

Renal

Transplant FailureIncreased

risk of

infection

Increased

risk of

malignancy

Complications

of

corticosteroid

therapy

 

   

Slide20

Complications of Withdrawal

of

Immunosuppression

 

Secondary adrenal insufficiency

Loss of residual renal function

Potentially adverse immunologic effects among those pursuing another transplantation

Requiring

transplant

nephrectomy

Slide21

Graft

Intolerance

Syndrome

Low

grade

fever

Flu

-

like

symptoms

Pain in the graft region

Hematuria

Tenderness and swelling of graft

Slide22

Graft intolerance syndrome is commonly seen in the first year.

Despite the different immunosuppressive treatment withdrawal protocols,

Graft

intolerance

syndorome

is

s

een

in 30-50% of

patients

.

Pham

PT,

Management

of

patients with a failed kidney transplant: Dialysis

reinitiation

,

immunosuppression

weaning, and

transplantectomy

. World J

Nephrol

2015

Slide23

Increased

graft

size

Elevated

C-

reactive

protein

Elevated

erythrocyte sedimentation rate

Elevated

f

erritin

levels

A

nemia

resistant

to

erythropoietin

therapy

Slide24

Treatment

options

Non

-

steroidal

anti-

inflammatory

drugs

Corticosteroids

Percutaneous

graft

embolization

Transplantectomy

Delgado

P.

Intolerante

syndrome

in

failed

renal

allografts

: incidence and efficacy of

percutaneous

embolization

.

Am J Kidney Dis 2005

Slide25

*

In

the

study

included

33

patients

having

Graft

intolerance

syndrome

.

*

Percutaneous

embolization

was

performed

in

the

treatment

of these patients

. * 85% of patients recovered after treatment with percutaneous embolization.* Percutaneous embolization in five (%15) patients failed and they required graft nephrectomi. * In this study, graft nephrectomy was recommended in patients who do not respond to percutaneous embolization. GONZAÂ LEZ-SATUE C, Percutaneous embolization of the failed renal allograft in patients with graft intolerance syndrome BJU International 2000

Slide26

In

the

study

made

by

Al

Badaai

et al.

Group 1

(32

patients

)

: patients who had

percutaneous

embolization

as first-line treatment

.

Group 2

(40

patients

)

: patients directly treated by surgical removal.

To avoid pain, patients

in

group

1

were given IV hydrocortisone

(100 mg x 4/day for 2–3 days) and analgesics.The success rate of percutaneous embolization treatment in Graft intolerans syndrome was 84.3%Nephrectomy was required in five patients.There were complications in two patients with percutaneous embolization. Complications developed in 14 patients made the nephrectomy.Al Badaai G, Renal graft intolerance syndrome in late graft failure patients: efficacy and safety of embolization as first-line treatment compared to surgical removal Transplant International 2017

Slide27

Delgado

et al.

diagnosed Graft

intoleras

syndrome in 55 of 149 patients returning to dialysis

.

The incidence of graft intolerance syndrome was found to be 37%

Vascular

embolization

was performed in 48 patients

.

65%

(31)

of patients after vascular

embolization

were successfully treated

.

Percutaneous

embolization

was repeated in 8 patients, being successful in 6 of them.

22% (11) of

patients

required

nephrectomy

in this study

.

Delgado

P et al.

Intolerance syndrome in

failed renal allografts:incidence and efficacy of percutaneous embolization. Am J Kidney Dis;2005;46:339

Slide28

In the study

,

Krause et al

.

published the treatment of the patient

(no:11)

with

Graft intolerance syndrome

.

Ten patients were treated with

indomethacin

(25 mg/day

for 10–14 days); in two patients

,

the treatment was successful

.

In five patients high-dose prednisone (1–2 mg/kg/day) was added to

indomethacin

and administered for 14

days with gradual tapering-off during 1–3 months.

Complete

remission was achieved in one patient

.

Seven patients

were

used

percutaneous embolization. Six patients were provided a remission.Krause I, Graft intolerance syndrome in children with failed kidney allografts—clinical presentation, treatment options and outcome Nephrol Dial Transplant 2008.

Slide29

Absolute and

R

elative

I

ndications

for

T

ransplantectomy

Absolute

indications

(

commonly

accepted

)

Primary

nonfunction

Hyperacute

rejection

Early

recalcitrant

acute

rejection

Early graft loss (generally defined as graft loss within the first year)

Arterial

or venous thrombosisGraft intolerance syndromeRecurrent urinary tract infections or sepsis/urosepsisMultiple retained failed transplants prior to a repeat transplantCancerRelative indications (controversial)The presence of hematologic or biochemical markers of the chronicinflammatory stateErythropoietin resistance anemiaElevated ferritin levelElevated C reactive proteinElevated erythrocyte sedimentation rateLow prealbumin/albuminGraft loss due to BK nephropathy and high level BK viremia Pham et al, Management of patients with a failed kidney transplant:Dialysis reinitiation

,

immunosuppression

weaning, and

transplantectomy

World J

Nephrol

2015, pp 148-159

Slide30

Immunosuppressive therapy in renal graft failure in patients returning to dialysis

Living

donor

kidney

recipients

;

Continue low-dose immunosuppressive therapy

Pham et al,

Management of patients with a failed kidney

transplant:Dialysis

reinitiation

,

immunosuppression

weaning, and

transplantectomy

World J

Nephrol

2015, pp 148-159

Slide31

Deceased

donor

kidney

recipients

If there is no renal residual function, immunosuppressive therapy is discontinued.

If the patient has renal residual function, the risk of complications is assessed.

If there is a risk of high complication, immunosuppressive therapy is

discontinued

.

If there is no risk of high complication, low-dose immunosuppressive therapy is continued.

Pham et al,

Management of patients with a failed kidney

transplant:Dialysis

reinitiation

,

immunosuppression

weaning, and

transplantectomy

World J

Nephrol

2015, pp 148-159

Slide32

Suggested

I

mmunosuppression

W

ithdrawal

P

rotocols

B

ased

on

M

aintenance

T

herapy

CNI +

antimetabolitea

+

prednisone

Discontinue

antimetabolite

at initiation of dialysis

Taper

CNI

over

4-6

wk

Maintain same steroid dose at initiation of dialysis

2-4 wk, then taper by 1 mg/mo (starting from 5 mg daily) until off.Pham et al, Management of patients with a failed kidney transplant:Dialysis reinitiation, immunosuppression weaning, andtransplantectomy World J Nephrol 2015, pp 148-159

Slide33

Suggested

I

mmunosuppression

W

ithdrawal

P

rotocols

B

ased

on

M

aintenance

T

herapy

CNI +

mTOR

inh

+

prednisone

Discontinue

mTOR

inh

at initiation of dialysis

Taper

CNI

over

4-6 wkMaintain same steroid dose at initiation of dialysis 2-4 wk, then taper by 1 mg/mo (starting from 5 mg daily) until offPham et al, Management of patients with a failed kidney transplant:Dialysis reinitiation, immunosuppression weaning, andtransplantectomy World J Nephrol 2015, pp 148-159

Slide34

Suggested

I

mmunosuppression

W

ithdrawal

P

rotocols

B

ased

on

M

aintenance

T

herapy

mTOR

inh

+

prednisone

Taper

mTOR

inh

over

4-6

wk

Maintain same steroid dose at initiation of dialysis 2-4 wk, then taper by 1 mg/mo (starting from 5 mg daily) until off.Pham et al, Management of patients with a failed kidney transplant:Dialysis reinitiation, immunosuppression weaning, andtransplantectomy World J Nephrol 2015, pp 148-159

Slide35

Immunosuppression W

eaning

P

rotocol

F

ollowing

kidney Transplant Failure and Return to

D

ialysis

A

ll

immunosuppression

apart

from

steroids

are

stopped

immediately

after

nephrectomy

.

Antiproliferative agents (

azathiopurine, mycophenolate) can be stopped immediately, followed by gradual taper of the CNI and mTOR inhibitor.Wean azathioprine or mycophenolate mofetil/mycophenolic acid off over 3 months; stop immediately with acute infection requiring hospitalization or IV antibiotics.Maintain prednisone 5 mg daily if plans to retransplant within 1 year of transplant failure or if residual renal function on 24-h urine provides for ≥0.5 mL/min urea clearance.Wean prednisone 1 mg/day per month to off if no plans to retransplant, no residual renal function or still on dialysis 6 months after kidney failure. Andrews PA, on behalf of the Standards Committee of the British Transplantation Society. Summary of the British Transplantation Society Guidelines for Management of the Failing Kidney Transplant. Transplantation 2014; 98: 1130–1133 Kassakian CT et al. Immunosupression in the failing and failed transplant kidney: optimizing outcome

Nephrol

Dial

Transplant

2016;31:1261-1269

.

Slide36

Canadian

authors

suggested

that patients returning to peritoneal dialysis may

benefit from continuing some

immunosuppression

,

to maintain residual renal function in the graft

.

Jassal

SV, et al.

Continued

transplant

immunosuppression

may prolong survival after return to peritoneal

dialysis: results of a decision analysis. Am J Kid

Dis

40:178–183, 2002