Transcript Anaemia in Tx-patients

OPTA – Education Initiative
OPTA – Optimal Treatment of Renal Anaemia
Improving the efficacy and efficiency
of renal anaemia therapy
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OPTA – Optimal Treatment of Renal Anaemia
Existing Recommendations
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OPTA – Haemodialysis Patients
OPTA – Therapy with Iron and Recombinant Human Erythropoietin
OPTA – Influence of Inflammation/Infection on Anaemia Therapy
OPTA – Patients with Chronic Kidney Disease
OPTA – Diabetic Patients with Chronic Kidney Disease
OPTA – Rationale
• European Best Practice Guidelines and KDOQI Guidelines
provide scientific evidence on optimal treatment of renal anaemia.
• European Surveys of Anaemia Management (ESAM I &II,
PRESAM, TRESAM) and Dialysis Outcomes and Practice
Patterns Study (DOPPS) demonstrate relevant gaps between
standards of care of anaemia treatment and daily practice.
• OPTA aims to transfer standards of care into daily practice and to
optimize efficacy and efficiency of anaemia therapy by focussing
on major and minor factors influencing treatment of renal
anaemia.
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OPTA – Optimal Treatment of Renal Anaemia
in Transplanted Patients
Faculty:
W. H. Hörl, Austria
Y. Vanrenterghem, Belgium
M. Arias, Spain
I. Boletis, Greece
N. Purlo, Russia
L. Rostaing, France
O. Viklicky, Czech Republic
C. Wanner, Germany
M. Zeier, Germany
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Content
• Prevalence of anaemia in transplanted patients
• Factors for development of anaemia
• Impact of anaemia on clinical outcomes
• Treatment of anaemia in transplanted patients
• Summary
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Anaemia in Tx-patients – Time for observation after
transplantation
• Early posttransplantation period
< 6 months after
transplantation
• Late posttransplantation period
> 6 months after
transplantation
(chronic phase)
• Posttransplant failure
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Prevalence of anaemia in Tx-patients (I/II)
Author
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Number of
patients
Definition
of anaemia
Mean
Hb (g/dl)
Hct (%)
Diagnosis of anaemia
after Tx and % of
anaemic patients
Saito, 1998
(Adults)
60
M < 12.8 g/dl
F < 11.5 g/dl
Average =
23%
Lorenz, 2002
(Adults)
438
M < 13 g/dl
F < 12 g/dl
Average =
39.7%
Mix 2003
(Adults)
240
M < 12 g/dl
F < 11 g/dl
38%
after 5
years
six months =
year 1 =
19.3%
19.8%
Mix 2003
(Adults)
240
Hct < 36%
38%
after 5
years
at transplantation =
year 1 =
year 4 =
76%
21%
36%
Prevalence of anaemia in Tx-patients (II/II)
Author
Definition
Mean
of anaemia Hb (g/dl)
Diagnosis of anaemia
after Tx and % of
anaemic patients
Vanrenterghem 4,263
2003
(Adults)
M < 13 g/dl
F < 12 g/dl
13.2 ±1.9
Average =
over 5 years
38.6%
Shibagaki,
2004
(Adults)
192
M < 13 g/dl
F < 12 g/dl
13 ± 0.1
6 months =
12 months =
M Hb ≤ 12 g/dl =
F Hb ≤ 11 g/dl =
41%
45%
20%
19%
Winkelmayer,
2004
(Adults)
374
Hct < 33%
38%
after 5
years
Average
7.7 years ± 6.79 =
28,6%
12.9 ±1.6
Prevalence of anaemia = 45.6%
Hb ≥ 10 g/dl < 11 g/dl = 8,2%
Hb < 10 g/dl =
3,3%
Shah, 2006
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Number of
patients
1.151
Prevalence of anaemia in Tx-patients
TRESAM – Transplant European Survey of Anaemia
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Vanrenterghem Y, Am J Transplant 2005;3:835–845.
Prevalence of anaemia in Tx-patients
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Vanrenterghem Y, Am J Transplant 2005;3:835–845.
Prevalence of anaemia in Tx-patients
Posttransplantation anaemia at 12 months in kidney recipients
treated with mycophenolate mofetil
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Imoagene-Oyedeji et al., J Am Soc Nephrol 2006;17:3240–3247.
Prevalence of anaemia in Tx-patients – Key note
• The prevalence of anaemia varies by time after transplantation
and by level of graft function.
• As transplanted patients are exposed to the additional risk factor
of immunosuppressive therapy, the relationship between
haemoglobin and eGFR may differ from those seen in other CKD
disorders.
• Due to the high prevalence of anaemia at any time after kidney
transplantation, patients should be followed up regularly for the
development of their haemoglobin level.¹,²
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1 Revised
2 K/DOQI,
EBPGs, NDT 2004;19.
Am J Kidney Dis 2001;37.
Diagnosis of anaemia in patients with chronic
kidney disease/Tx-patients
Patients should receive a diagnostic work-up for anaemia
• When creatinine clearance falls below
– 70 ml/min in man
– 50 ml/min in women
• When Hb-level falls below:
– 11.5 g/dL in adult female patients1
– 13.5 g/dL in adult male patients1
– 12 g/dL in adult male patients aged > 701
– 11 g/dL in pre-pubertal subjects and pre-menopausal females2
– 12 g/dL in adult males and post-menopausal females2
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1Revised
2K/DOQI,
EBPGs, NDT 2004;19.
Am J Kidney Dis 2001;37.
Factors for development of anaemia in Tx-patients
• Kidney/Renal graft function (serum creatinine/eGFR)
• Endogenous erythropoietin levels
• Iron deficiency
• Exposure to immunosuppressive agents and antiviral medication
• Acute rejections
• Resistance to ESAs due to infection/inflammation
• Blood loss (perisurgical, frequency of blood draws)
• Other factors
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Factors for development of anaemia in Tx-patients
Kidney/renal graft function (serum creatinine/eGFR)
• strongest individual predictor of development of haemoglobin level
Serum creatinine >2 mg/dL:
two times more likely
to be anaemic (60% vs 30%)1
Endogenous erythropoietin levels
• Endogenous erythropoietin deficiency due to insufficient function of
transplanted graft after Tx
• Decrease in erythropoietin production due to acute rejection
• Insufficient endogenous EPO-level to overcome bone marrow
suppression (immunosuppressants, antivirals, viral infections)
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¹Vanrenterghem Y, Am J Transplant 2005;3:835–845.
Factors for development of anaemia in Tx-patients
Iron Deficiency
Absolute iron deficiency
• Perisurgical blood loss
• Depleted iron stores
• Increased erythropoiesis after surgery
• Inhibited intestinal iron absorption due to inflammation/infection
• Stress induced GI-bleeding
Functional iron deficiency
• Chronic inflammation
• Uraemia
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Factors for development of anaemia in Tx-patients
Exposure to immunosuppressive agents and antiviral medication
Bone marrow suppression
• Immunosuppressives
• Antivirals/Antibacterials
AZA, MMF, Sirolismus,
Corticosteroids
Ganciclovir,
Trimethoprim-Sulfamethoxazole
Haemolysis and thrombotic microangiopathy:
• Cyclosporine, Tacrolismus, Sirolismus, Antithymocyte Globulin (ATG)
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Factors for development of anaemia in Tx-patients
Resistance to ESAs due to infection/inflammation
• Anaemia of chronic disease
• CMV-infection
• Parvovirus B19
– aplastic anaemia
– pure red cell aplasia
• High inflammatory state
Blood loss
• Surgery
• High frequency of blood draws
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Factors for development of anaemia in Tx-patients
Other factors
The influence of the following factors is discussed controversially
and the available clinical data are not yet conclusive
• ACE and ARBs
• Age of donor
• Age of recipient
• Gender
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Factors for development of anaemia in Tx-patients –
Key note
• Decreased kidney/graft function
• Decreased endogenous erythropoietin production due to
malfunctioning graft or acute rejection
• Depleted iron stones due to perisurgical blood loss and
decreased erythropoiesis in the posttransplantation period up to 6
months
• Immunosuppressive agents and antiviral/antimicrobial medication
• Increased resistance to ESAs due to acute or chronic rejection,
inflammation or viral infections
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Quelle
Impact of anaemia on clinical outcomes in Tx-patients
Posttransplantation anaemia is associated with various
potential consequences for the transplanted patients:
• All-cause mortality
• Graft rejection
• Graft failure
• Congestive heart failure
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Potential mechanisms for impact of anaemia
in Tx-patients (I/II)
All-cause mortality
• Inadequate tissue perfusion/cellular hypoxia
• Hyperkinetic circulation
• Increased thickness of left ventricular wall
• Congestive heart failure
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Potential mechanisms for impact of anaemia
in Tx-patients (II/II)
Graft failure
• Reduced oxygen delivery to tissue
• Oxidative stress insulting renal tissues
• Chronic hypoxia and oxidative stress are profibrogenic stimuli
for tubular cells and interstitial fibroblasts
• Release of proinflammatory cytokines that recruit inflammatory
cells in the interstitium
• Hypoxic damage may be potentiated by use of
immunosuppressive agents
• Reduced renal blood flow due to concomittant CHF
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Impact of anaemia on clinical outcomes in Tx-patients
Anaemia and patient survival (N=1023)
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Chhabra et al., Clin J Am Soc Nephrology 2008;1168–1174.
Impact of anaemia on clinical outcomes in Tx-patients
Anaemia and patient survival (N=938)
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Molnar et al., AJT 2007;7:818–824.
Impact of anaemia on clinical outcomes in Tx-patients
Anaemia and patient survival (N=626)
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Imoagene-Oyedeji et al., J Am Soc Nephrol 2006;17:3240–3247.
Impact of anaemia on clinical outcomes in Tx-patients
Anaemia and acute rejection (N=1023)
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Chhabra et al., Clin J Am Soc Nephrology 2008:1168–1174.
Impact of anaemia on clinical outcomes in Tx-patients
Anaemia and graft survival (N=1023)
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Chhabra et al., Clin J Am Soc Nephrology 2008:1168–1174.
Impact of anaemia on clinical outcomes in Tx-patients
Anaemia and graft survival
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Molnar et al., AJT 2007;7:818–824.
Impact of anaemia on clinical outcomes in Tx-patients
Increased risk for congestive heart failure (N=638)
Relative hazard (risk) of de novo CHF as a function of hemoglobin quartile in a cohort of 638 renal transplant recipients (RTR) alive with
functioning graft and free of clinical heart disease at 1 yr posttransplant.
*Adjusted for age, diabetes, systolic BP, donor status, and serum albumin.
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Rigatto et al., J Am Soc Nephrol 2002;13:1084–1090.
Impact of anaemia in Tx-patients – Key note
Anaemia has a significant impact on patients with kidney
transplantation. Posttransplantation anaemia is associated
with:
• Decreased patient survival1,2,3
• Increased graft rejection1
• Decreased graft survival1,2,3,4
• Increased risk for congestive heart failure5
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¹ Chhabra et al., Clin J Am Soc Nephrol 2008;3:1168–1174.
² Molnar et al., Am J Transplant 2007;7:818–824.
³ Imoagene-Oyedeji et al., J Am Soc Nephrol 2006;17:3240–3247.
⁴ Winkelmayer et al., Nephrol Dial Transplant 2006;21:3559–3566.
⁵ Rigatto et al., J Am Soc Nephrol 2002;13:1084–1090.
Treatment of anaemia in Tx-patients
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1. Early postransplantation period
< 6 months after transplantation
2. Late posttransplantation period
(chronic phase)
> 6 months after transplantation
Treatment of anaemia in Tx-patients
Early posttransplantation period (< 6 months after transplantation)
• Only two studies with limited patient numbers have been performed.1, 2
• One investigator concluded that ESAs could correct anaemia despite
relative EPO-resistance, the other investigator saw no relevant clinical
impact of ESA-treatment.
• No significant adverse events were reported in both studies.
• In a third, retrospective study, early ESA treatment (one week after
Tx) was associated with new onset of hypertension.3
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¹Van Loo A et al., Nephrol Dial Transplant 1996;11(9):1815–1821.
²Van Biesen W et al., Transplantation. 2005;79(3):367–368.
³Nagarajan S et al., Clin Transplant 2007;21:597–608.
Treatment of anaemia in Tx-patients
Late posttransplantation period (> 6 months after transplantation)
• In the late posttransplant period, renal anaemia is easily corrected by
ESA therapy.¹
• ESA therapy may rapidly lead to iron deficiency.²
• A decreased response to ESA treatment may be anticipated due to
myelosuppressive medication or/and chronic inflammation.
• ESA therapy is save, however, hypertension as potential side effect
of ESA therapy should be considered.
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¹El Haggan W, Vallet L, Hurault de Ligny B, et al., Transplantation 2004;77:1914–1915.
²Hörl WH, J Am Soc Nephrol 2007;18:382–393.
Treatment of anaemia in Tx-patients (I/II)
Guidelines and target Hb-levels
• General guidelines for the treatment of anaemia in Tx-patients
have not been developped
• Target Hb levels of renal transplant patients need to be defined
• Revised EBPGs recommend to start anaemia treatment when
Hb-level falls below 11 g/dl
• Revised K/DOQI guidelines recommend to keep the Hb in the
range of 10–12 g/dl
• EMEA recommends a target Hb level of 10–12 g/dl
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Treatment of anaemia in Tx-patients (II/II)
• Inflammatory state of Tx-patients and immunosuppressive
medication may increase resistance to ESA therapy.
• ESAs are safe and effective in correcting anaemia during the
early and late posttranspantation period. Hypertension should be
considered as potential adverse event and therefore be monitored
in regular intervals.
• In early posttransplant period, anaemia treatement has to be
decided on an individual patient base, as several patients show
recovery from anaemia without ESA treatment.
• Blood transfusions should be avoided.
• Initiation of ESA treatment could rapidly lead to iron deficiency.
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Summary (I/II)
• Anaemia has a high prevalence in Tx-patients. Patients in
CKD-stages 3–5 T should be followed regularly for their Hb-level due to
the high risk for anaemia development and anaemia associated
complications.
• Graft function, immunosuppressive drugs, iron deficiency, decreased
endogenous erythropoietin levels and resistance to ESA treatment
(infections, graft rejections) are the main drivers for the development of
anaemia in Tx-patients.
• Anaemia in Tx-patients is significantly associated with increased overall
mortality, increased rate of allograft loss, increased CHF and increased
rate of acute rejection. Even when prospective randomized trials will alter
the actual data base, anaemia in Tx-patients requests a high level of
nephrologists attention.
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Summary (II/II)
• Treatment of anaemia in Tx-patients is effective.
In the early posttransplantation period, decision on anaemia treatment
has to be made on an individual patient base, as several patients show
recovery from anaemia without ESA treatment.
• Target Hb-level should be kept in the range of 11–12 g/dL (Revised
EBPGs) or 10–12 g/dL (K/DOQI).
• ESA treatment in Tx-patients is safe. Hypertension should be considered
as potential adverse event and therefore be monitored in regular
intervals.
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