OPTA – Education Initiative

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OPTA Education Initiative

• OPTA Optimal Treatment of Renal
  AnaemiaImproving the efficacy and efficiencyof
  renal anaemia therapy

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OPTA Optimal Treatment of Renal Anaemia

• Existing Recommendations
• 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

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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 Anaemiain
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 lt 6
  months after transplantation
• Late posttransplantation period gt 6
  months after transplantation (chronic
  phase)
• Posttransplant failure

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Prevalence of anaemia in Tx-patients (I/II)
Author Number of Definition Mean Diagnosis of
anaemia patients of anaemia Hb (g/dl) after Tx
and of Hct () anaemic patients Saito,
1998 60 M lt 12.8 g/dl Average 23(Adults) F
lt 11.5 g/dl Lorenz, 2002 438 M lt 13
g/dl Average 39.7(Adults) F lt 12 g/dl Mix
2003 240 M lt 12 g/dl 38 six months
19.3(Adults) F lt 11 g/dl after 5 year 1
19.8 years Mix 2003 240 Hct lt 36 38 at
transplantation 76(Adults) after 5 year 1
21 years year 4 36
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Prevalence of anaemia in Tx-patients (II/II)
Author Number of Definition Mean Diagnosis of
anaemia patients of anaemia Hb (g/dl) after Tx
and of anaemic patients Vanrenterghem
4,263 M lt 13 g/dl 13.2 1.9 Average
38.62003 F lt 12 g/dl over 5
years(Adults) Shibagaki, 192 M lt 13 g/dl 13
0.1 6 months 412004 F lt 12 g/dl 12
months 45(Adults) M Hb 12 g/dl
20 F Hb 11 g/dl 19 Winkelmayer, 374 H
ct lt 33 38 Average 2004 after 5 7.7 years
6.79 28,6(Adults) years Shah,
2006 1.151 12.9 1.6 Prevalence of anaemia
45.6 Hb 10 g/dl lt 11 g/dl 8,2 Hb lt
10 g/dl 3,3
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Prevalence of anaemia in Tx-patients TRESAM
Transplant European Survey of Anaemia
Vanrenterghem Y, Am J Transplant 20053835845.
10
Prevalence of anaemia in Tx-patients
Vanrenterghem Y, Am J Transplant 20053835845.
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Prevalence of anaemia in Tx-patients

• Posttransplantation anaemia at 12 months in
  kidney recipients
• treated with mycophenolate mofetil

Imoagene-Oyedeji et al., J Am Soc Nephrol
20061732403247.
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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

1 Revised EBPGs, NDT 200419. 2 K/DOQI, Am J
Kidney Dis 200137.
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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 gt 701
• 11 g/dL in pre-pubertal subjects and
  pre-menopausal females2
• 12 g/dL in adult males and post-menopausal
  females2

1Revised EBPGs, NDT 200419.2K/DOQI, Am J Kidney
Dis 200137.
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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 gt2 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)

¹Vanrenterghem Y, Am J Transplant 20053835845.
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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 AZA, MMF, Sirolismus,
  Corticosteroids
• Antivirals/Antibacterials 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/antimicrobi
  al medication
• Increased resistance to ESAs due to acute or
  chronic rejection, inflammation or viral
  infections

Quelle
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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 (N1023)

Chhabra et al., Clin J Am Soc Nephrology
200811681174.
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Impact of anaemia on clinical outcomes in
Tx-patients
Anaemia and patient survival (N938)
Molnar et al., AJT 20077818824.
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Impact of anaemia on clinical outcomes in
Tx-patients
Anaemia and patient survival (N626)
Imoagene-Oyedeji et al., J Am Soc Nephrol
20061732403247.
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Impact of anaemia on clinical outcomes in
Tx-patients
Anaemia and acute rejection (N1023)
Chhabra et al., Clin J Am Soc Nephrology
200811681174.
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Impact of anaemia on clinical outcomes in
Tx-patients
Anaemia and graft survival (N1023)
Chhabra et al., Clin J Am Soc Nephrology
200811681174.
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Impact of anaemia on clinical outcomes in
Tx-patients
Anaemia and graft survival
Molnar et al., AJT 20077818824.
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Impact of anaemia on clinical outcomes in
Tx-patients
Increased risk for congestive heart failure
(N638)
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.
Rigatto et al., J Am Soc Nephrol
20021310841090.
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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

¹ Chhabra et al., Clin J Am Soc Nephrol
2008311681174.² Molnar et al., Am J
Transplant 20077818824.³ Imoagene-Oyedeji et
al., J Am Soc Nephrol 20061732403247.4
Winkelmayer et al., Nephrol Dial Transplant
20062135593566.5 Rigatto et al., J Am Soc
Nephrol 20021310841090.
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Treatment of anaemia in Tx-patients

• 1. Early postransplantation period lt 6 months
  after transplantation
• 2. Late posttransplantation period gt 6 months
  after transplantation (chronic phase)

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Treatment of anaemia in Tx-patients

• Early posttransplantation period (lt 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

¹Van Loo A et al., Nephrol Dial Transplant
199611(9)18151821. ²Van Biesen W et al.,
Transplantation. 200579(3)367368.³Nagarajan S
et al., Clin Transplant 200721597608.
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Treatment of anaemia in Tx-patients

• Late posttransplantation period (gt 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.

¹El Haggan W, Vallet L, Hurault de Ligny B, et
al., Transplantation 20047719141915.²Hörl WH,
J Am Soc Nephrol 200718382393.
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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 1012 g/dl
• EMEA recommends a target Hb level of 1012 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 35 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
  1112 g/dL (Revised EBPGs) or 1012 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.