Can Huzmeli Necip Fazıl City Hospital Kahramanmaras Turkey 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 ID: 932622
Download Presentation The PPT/PDF document "Erythropoietin Resistance from Failed Re..." is the property of its rightful owner. Permission is granted to download and print the materials on this web site for personal, non-commercial use only, and to display it on your personal computer provided you do not modify the materials and that you retain all copyright notices contained in the materials. By downloading content from our website, you accept the terms of this agreement.
Slide1
Erythropoietin Resistance from Failed Renal Allograft: Case Report
Can Huzmeli
Necip Fazıl
City
Hospital
Kahramanmaras
/
Turkey
Slide2Anemia 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.
Slide3Erythropoietin 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
Slide4Erythropoietin 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
Slide5Risk 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
Slide6Risk
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
Slide7Case
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
Slide8Case
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
Slide9Semptoms
Fever
weakness
Fatigue
Sensitivity in the graft region
Slide10Laboratory
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
Slide11Hematuria
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
.
Slide12The 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.
Slide14Distribution 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
Slide15Distribution 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
Slide16Mortality
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
Slide17Anemia
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
Slide18Continuation 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
Slide19Reasons for
Withdrawal
of
Immunosuppression
After
Renal
Transplant FailureIncreased
risk of
infection
Increased
risk of
malignancy
Complications
of
corticosteroid
therapy
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
Slide21Graft
Intolerance
Syndrome
Low
grade
fever
Flu
-
like
symptoms
Pain in the graft region
Hematuria
Tenderness and swelling of graft
Slide22Graft 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
Slide23Increased
graft
size
Elevated
C-
reactive
protein
Elevated
erythrocyte sedimentation rate
Elevated
f
erritin
levels
A
nemia
resistant
to
erythropoietin
therapy
Slide24Treatment
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
Slide26In
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
Slide27Delgado
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
Slide28In 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.
Slide29Absolute 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
Slide30Immunosuppressive 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
Slide31Deceased
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
Slide32Suggested
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
Slide33Suggested
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
Slide34Suggested
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
Slide35Immunosuppression 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
.
Slide36Canadian
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