Effects of Anemia Correction on Vascular and Monocyte Function in Renal Transplant Recipients
Condition: Kidney Transplantation; Anemia
MeSH terms: Anemia
Study type: Interventional
Phase: Phase 4

Summary: 
      Correction of anaemia in renal transplant recipients by parenteral application of recombinant
      erythropoietin and if necessary iron will improve large artery function (endothelial function
      and elasticity), as assessed by ultrasound techniques and applanation tonometry.

      The changes in large artery function will be reflected by changes in serological markers of
      endothelial function and oxidative stress and by changes in monocyte function and apoptosis.

      There are gender differences in the responses of vascular function to correction of anemia.

      Besides improvement of large artery function, correction of anemia will also affect
      parameters of graft function, i.e. glomerular and tubular proteinuria.
    

Detailed description: 
      The value of anaemia therapy with recombinant erythropoietin and iron for improvement of
      cardiovascular outcome has been clearly demonstrated in dialysis patients and is standard of
      care. In this patient collective one study shows that correction of anaemia together with
      blood pressure control does improve large artery function. After kidney transplantation, the
      situation is not clear. Anemia is common in kidney transplant patients despite a functioning
      graft and is caused by inadequate erythropoietin production, inflammatory reactions and toxic
      bone marrow depression. Current guidelines suggest to correct anemia also in kidney
      transplant recipients in analogy to hemodialysis patients, however, there is to date no
      evidence that correction of mild to moderate anemia will improve cardiovascular outcome.
      Since cardiovascular outcome studies are difficult to perform in renal transplant patients we
      propose to study intermediate endpoints, surrogate parameters of cardiovascular endpoints,
      i.e. large artery distensibility and endothelium-dependent brachial artery dilatation. Our
      group was able to show that the former is a valid marker of cardiovascular morbidity in renal
      transplant patients (1), and a recent report stated the same prognostic value for brachial
      artery flow-dependent dilatation in hemodialysis patients. Since the causes of anemia in
      renal transplant patients are complex, it is not clear that treatment of at anemia with
      recombinant erythropoietin and iron will be beneficial. Erythropoetin treatment is likely to
      improve hypoxia and thereby to improve large artery function, but also upregulates
      circulating endothelial progenitor cells, already elevated in kidney transplant patients and
      a marker of vascular stress, e.g. in patients with vasculitis. Erythropoietin might therefore
      be detrimental to endothelial function and as a consequence to vascular elasticity. It may be
      argued that in renal transplant patients, vascular damage is profound and irreversible and
      therefore vascular function does not respond to pharmacological interventions. However, our
      group was able to show that although renal transplant patients have severely impaired large
      artery functional wall properties independent of immunosuppressive treatment regimens (2),
      they have a preserved large artery vasodilator capacity (3) and that treatment with a statin
      produces sustained long-term improvements of endothelial function in kidney transplant
      patients (4). Previous studies showed effects of erythropoietin treatment on serological
      parameters of endothelial function in hemodialysis patients. It is important to relate
      erythropoietin-induced changes in these parameters to changes in large artery function.
      Particularly, in the aimed target population immunological processes are very likely to
      affect vascular function. It has been shown that endothelial cell proliferation is induced by
      angiogenetic factors released by activated monocytes. Besides monocyte adhesion to
      endothelial cells is triggered e.g. by endothelial cells themselves when they are exposed to
      shear stress(5). During the adhesion process different costimulatory factors become important
      in the early and critical atherogenetic event. Monocyte survival and activation do have a key
      role in this process leading to arteriosclerosis and endothelial damage(6). Changes in
      monocyte survival in dependence of immunosuppression or erythropoietin treatment may be
      responsible for increasing circulating endothelial cells(7). Therefore we aim to relate
      erythropoietin-induced changes in vascular function to changes in monocyte function and
      apoptosis. In many disease states changes in endothelial function are reflected by changes in
      urinary protein excretion. Therefore, erythropoietin therapy could alter urinary protein
      excretion in parallel to the changes observed in large artery function. Finally, anemia is
      more common in female renal transplant recipients than in male renal transplant recipients,
      and female dialysis patients tend to require more erythropoietin for anemia treatment that
      male patients. Therefore it is conceivable that gender differences exist with respect to the
      effects of anemia correction on vascular function.

        1. Barenbrock, M., M. Kosch, E. Joster, K. Kisters, K. H. Rahn, and M. Hausberg. Reduced
           arterial distensibility is a predictor of cardiovascular disease in patients after renal
           transplantation. J.Hypertens. 2002, 20: 79-84

        2. Kosch M, Hausberg M, Suwelack B. Studies on effects of calcineurin inhibitor withdrawal
           on arterial distensibility and endothelial function in renal transplant recipient.
           Transplantation 2003, 76:1516-9.

        3. Hausberg M, Kisters K, Kosch M, Rahn KH, Barenbrock M. Flow-mediated vasodilation and
           distensibility of the brachial artery in renal allograft recipients. Kidney Int 1999,
           55: 1104-1110

        4. Kosch M, Barenbrock M, Suwelack B, Schaefer RM, Rahn KH, Hausberg M. Effect of a 3-year
           therapy with the 3-hydroxy-3-methylglutaryl coenzyme a reductase-inhibitor fluvastatin
           on endothelial function and distensibility of large arteries in hypercholesterolemic
           renal transplant recipient. Am J Kidney Dis. 2003, 41:1088-96

        5. Hwang J, Saha A, Boo YC, Sorescu GP, McNally JS, Holland SM, Dikalov S, Giddens DP,
           Griendling KK, Harrison DG, Jo H. Oscillatory shear stress stimulates endothelial
           production of O2- from p47phox-dependent NAD(P)H oxidases, leading to monocyte adhesion.
           J Biol Chem. 2003,278(47): 47291-47298.

        6. Österud A, Björklid E. Role of monocytes in atherogenesis. Physiological reviews, 2003,
           83: 1069-1112.

        7. Bahlmann FH, DeGroot K, Duckert T, Niemczyk E, Bahlmann E, Boehm SM, Haller H, Fliser D.
           Endothelial progenitor cell proliferation and differentiation is regulated by
           erythropoietin. Kidney Int. 2003; 64:1648-1652.
    

Intervention name(s): darbopoeitin
Intervention type(s): Drug
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Kidney transplantation; anemia; vascular endothelium; monocytes; apoptosis