OPTA – Education Initiative

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OPTA – Education Initiative

OPTA – Optimal Treatment of Renal Anaemia

Improving 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 < 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 Number of Definition Mean Diagnosis of anaemiapatients of anaemia Hb (g/dl) after Tx and % of

Hct (%) anaemic patients

Saito, 1998 60 M < 12.8 g/dl Average = 23%(Adults) F < 11.5 g/dl

Lorenz, 2002 438 M < 13 g/dl Average = 39.7%(Adults) F < 12 g/dl

Mix 2003 240 M < 12 g/dl 38% six months = 19.3%(Adults) F < 11 g/dl after 5 year 1 = 19.8%

years

Mix 2003 240 Hct < 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 anaemiapatients of anaemia Hb (g/dl) after Tx and % of

anaemic patients

Vanrenterghem 4,263 M < 13 g/dl 13.2 ±1.9 Average = 38.6%2003 F < 12 g/dl over 5 years(Adults)

Shibagaki, 192 M < 13 g/dl 13 ± 0.1 6 months = 41%2004 F < 12 g/dl 12 months = 45%(Adults) M Hb ≤ 12 g/dl = 20%

F Hb ≤ 11 g/dl = 19%

Winkelmayer, 374 Hct < 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 < 11 g/dl = 8,2%Hb < 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 2005;3:835–845.

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Prevalence of anaemia in Tx-patients

Vanrenterghem Y, Am J Transplant 2005;3:835–845.

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Prevalence of anaemia in Tx-patients

Imoagene-Oyedeji et al., J Am Soc Nephrol 2006;17:3240–3247.

Posttransplantation anaemia at 12 months in kidney recipientstreated with mycophenolate mofetil

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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 2004;19.2 K/DOQI, Am J Kidney Dis 2001;37.

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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 > 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 2004;19.2K/DOQI, Am J Kidney Dis 2001;37.

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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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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)

¹Vanrenterghem Y, Am J Transplant 2005;3:835–845.

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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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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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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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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

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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Anaemia and patient survival (N=1023)

Chhabra et al., Clin J Am Soc Nephrology 2008;1168–1174.

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Molnar et al., AJT 2007;7:818–824.


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Imoagene-Oyedeji et al., J Am Soc Nephrol 2006;17:3240–3247.


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Chhabra et al., Clin J Am Soc Nephrology 2008:1168–1174.

Anaemia and acute rejection (N=1023)

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Chhabra et al., Clin J Am Soc Nephrology 2008:1168–1174.

Anaemia and graft survival (N=1023)

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Molnar et al., AJT 2007;7:818–824.

Anaemia and graft survival

30 Rigatto et al., J Am Soc Nephrol 2002;13:1084–1090.

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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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 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.

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Treatment of anaemia in Tx-patients

1. Early postransplantation period < 6 months after transplantation

2. Late posttransplantation period > 6 months after transplantation (chronic phase)

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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

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.

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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.

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.

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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 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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OPTA – Education Initiative

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