Sinnamon_edit.qxp 8/2/08 10:13 Page 32
Anaemia Management
compared the prevalence of anaemia between a cohort of 851 kidney Calcineurin Inhibitors
transplant recipients and a cohort of the general population with similar The calcineurin inhibitors (CNIs) ciclosporine A and tacrolimus act by
kidney function. For a given level of renal function, the transplant forming a complex with their respective cytoplasmic receptor proteins,
patients had a ‘dramatic excess’ of anaemia compared with the non- which subsequently bind to and inhibit calcineurin, thus impairing the
transplanted individuals. Factors other than renal function must therefore expression of several cytokine genes that promote T-cell activation.
contribute to PTA. They do not cause myelosuppression to the same degree as
azathioprine and their effects on bone marrow turnover in clinical
Immunosuppressive Medications practice are small.
17
Winkelmayer and colleagues
11
found that
Immunosuppressive agents have the propensity to cause bone tacrolimus was associated with lower HCT levels on multivariate
marrow suppression. Determining causation of anaemia by one analysis (-2.32%, 95% CI -4.23 to -0.41; p=0.02). Other studies report
immunosuppressant is difficult when using retrospective data due to the contrary findings.
6,7,10
presence of multiple confounding variables. For example, these
medications are generally used in combination and at varying doses. Sirolimus
Antirejection regimens are also likely to be altered in light of declining Sirolimus is a macrolide that also binds to a cytoplasmic-binding
renal function, which may in itself cause anaemia. protein. This ligand then blocks target of rapamycin (TOR), a regulatory
kinase, reducing cell proliferation. It affects both haematopoietic and
Azathioprine and Mycophenolate Mofetil non-haematopoietic cells. Augustine and colleagues
21
evaluated 214
Azathioprine (AZA), a well-established immunosuppressive agent, can kidney or kidney–pancreas transplant recipients who were treated with
cause leucopoenia, thrombocytopoenia, macrocytosis and anaemia. The an MMF-based (n=127) or sirolimus-based (n=87) immunosuppressive
newer drug mycophenoalte mofetil (MMF) is a potent inhibitor of de regimen for 12 months after transplantation. Adjunctive immuno-
novo purine synthesis affecting both T- and B-lymphocyte proliferation. suppressants – prednisolone and CNIs – were used in both groups.
Theoretically, erythrocytosis should not be interrupted as there is a Anaemia was defined as Hb <12g/dl for women and Hb<13g/dl for
salvage pathway available for red cell production.
17
However, both red men. The average dose of MMF at one year was 1.74±0.3g/day and of
and white cell lines appear to be suppressed in clinical practice. Both sirolimus 4.1±1.2mg/day, aiming for trough levels of 8–12ng/ml. At 12
MMF and AZA have been implicated in PTA. months, 31% of the MMF group and 57% of the sirolimus group
(p<0.001) were anaemic, with an average Hb of 13.6±2 and
In the study by Yorgin and colleagues, anaemia was significantly more 12.1±2g/dl, respectively (p<0.01). However, the estimated GFR (eGFR)
likely in those receiving MMF at five years after engraftment.
6
However, was also significantly lower in the sirolimus group (63±23 versus
when directly comparing the combination of ciclosporine + prednisolone 75±25ml/min; p<0.001), suggesting that poorer graft function may
+ MMF with ciclosporine + prednisolone + AZA by an intention-to-treat have been an additional factor in the development of anaemia in this
analysis, the only difference in the diagnosis of anaemia was at four years group. A recent report suggests that the improvement in GFR
(35.7 versus 10.2%; p=0.04). Five of the eight patients who converted following the withdrawal of ciclosporine may mitigate the anaemia-
from AZA to MMF also developed anaemia. From these data it is difficult inducing effect of sirolimus.
22
In this study 430 renal transplant
to state with any certainty whether MMF offers any additional risk of PTA patients were randomised at three months after engraftment to
over AZA. continue with triple therapy (sirolimus, ciclosporine and prednisolone)
or to have ciclosporine withdrawn. At five years only 39.1% of the
In the TRESAM study, those individuals receiving any immunosuppressive triple-therapy group had a normal Hb level compared with 68.5% of
combination that included MMF had a lower Hb compared with patients the ciclosporine withdrawal group, despite this latter group having a
not receiving MMF (13.1±1.9 versus 13.4±2.0g/dl; p<0.01).
7
Although two-fold higher sirolimus exposure. Anaemia was also more prevalent
statistically significant, these differences were small. Azathioprine use was in patients receiving sirolimus therapy in the study by Al-Khoury and
not related to PTA in the total patient population; however, a significant colleagues,
13
but the authors felt that this may have reflected poorer
difference in Hb levels (0.2g/dl; p<0.05) was found between patients graft function in these individuals.
treated with or without AZA in those with creatinine <2mg/dl
(<176mmol/l). Overall, the use of MMF or AZA was associated with an Blockade of the Renin–Angiotensin–Aldosterone Axis
odds ratio (OR) of 1.24 for being anaemic. In addition, Winkelmayer and Angiotensin-coverting enzyme inhibitors (ACEis) and angiotension II
colleagues
11
found MMF to be associated with lower HCT levels (-1.34%, receptor blockers (ARBs) have been used successfully in the management
95% confidence interval (CI) -2.65 to -0.02; p=0.05). Other studies report of post-transplant erythrocytosis and have the potential to cause PTA.
similar results.
13,14
MMF alone or in combination with tacrolimus was They are used frequently in the post-transplant population for a variety of
associated with an increased risk of PTA and transfusion in the immediate reasons, including hypertension control, cardioprotection and
post-operative period in the study by Ourahama and co-workers.
18
renoprotection in proteinuric individuals. It is therefore likely that they are
prescribed to those individuals with established renal impairment with
However, in contrast Mix and co-workers
10
and Sinnamon and the aim of preventing further deterioration. The studies to date
colleagues
19
found no significant association between baseline demonstrate conflicting results. Winkelmayer and co-authors
11
report an
immunosuppression regimen and anaemia following transplantation. independent association of ACEi with anaemia. A lower HCT was found
Khosroshahi and colleagues
20
studied the effects of MMF and AZA in 80 in those receiving this therapy (29.7% of patients) compared with those
renal transplant recipients and – in contrast to other studies – reported who were ACEi-naïve (-1.62%, 95% CI -2.71 to -0.54; p=0.003). A
higher Hb at one and six months following transplantation in those who similar trend was seen in those prescribed an ARB – 6.4% of this
had received MMF. transplant population – but this did not reach statistical significance. In
32 EUROPEAN RENAL DISEASE 2007