NDT Advance Access originally published online on April 4, 2006
Nephrology Dialysis Transplantation 2006 21(7):1974-1980; doi:10.1093/ndt/gfl121
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© The Author [2006]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Original Articles: Dialysis and Transplantation
Post-transplantation anaemia in adult and paediatric renal allograft recipients—Guy's Hospital experience
1 Adult and 2 Paediatric Renal Transplantation Units, Guy's Hospital, London, UK and 3 Parham Hospital, Lasé, Romania
Correspondence and offprint requests to: Dr David Goldsmith, FRCP, Consultant Nephrologist, Department of Renal Medicine and Transplantation, Guy's Hospital, St Thomas’ Street, London SE1 9RT, UK. Email: David.goldsmith{at}gstt.sthames.nhs.uk
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Abstract |
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Background. The commonest cause of renal transplant loss is death with a functioning graft, usually from an excess of cardiovascular disease (CVD). Anaemia is becoming increasingly recognized as a reversible risk factor for the development of CVD. The purpose of this study was to estimate the prevalence of post-transplantation anaemia (PTA) in a large population of stable adult and paediatric renal transplants in one centre and to correlate the estimated glomerular filtration rate (eGFR), iron indices and the use of immunosuppressants with the prevalence of anaemia.
Methods. Every adult and paediatric patient with a functioning renal transplant and more than 3 months post-engraftment at Guy's hospital, London, as of 31 December 2004 and who had a valid creatinine and haemoglobin, in the period 1 September–31 December 2004 inclusive, was identified. A large database of clinical and biochemical indices was built up on the basis of medical notes and electronic patient records. Results were analysed for the prevalence of anaemia and risk factors for its development. Anaemia was defined according to the WHO criteria. All patients on treatment with an erythropoiesis stimulating agent were classified as anaemic, irrespective of haemoglobin.
Results. A total of 878 adults and 73 children were identified. Mean haemoglobin in adults was 12.9±1.6 g/dl and 11.8±1.4 g/dl in the children. Mean eGFR was 49.3±20.1 ml/min in adults and 65.7±18.8 ml/min in the paediatric cohort. Haemoglobin correlated positively with the eGFR in both cohorts (R = 0.33 and 0.29 in adults and children, respectively (P<0.0001 for both)). We identified anaemia in 45.3% of adults and 22% in children. Ferritin levels were lower in children than in adults (79±93 vs 204±353 mg/l), but were higher in both cohorts among the non-anaemic populations than in those with anaemia. 58% of adults taking mycophenolate mofetil (MMF) were anaemic compared with 22% of children. One child, and 68 adults, were on recombinant erythropoietin. Multiple regression analyses identified age, female gender, eGFR and serum ferritin levels as independent predictors of haemoglobin in adult subjects.
Conclusions. The prevalence of PTA was high in both adult and paediatric cohorts while comparatively few patients were being treated with erythropoiesis stimulating agents. The strongest predictors of haemoglobin in this cohort of patients were age, female sex and graft function. Immunosuppression including MMF or sirolimus was associated with a higher prevalence of anaemia, but this was likely to be the result of poorer graft function in these subjects. Iron deficiency did not seem to be a causative factor for anaemia in this population.
Keywords: adult; age; female sex; ferritin; graft function; mycophenolate mofetil; paediatric; post-transplantation anaemia; sirolimus
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Introduction |
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In the context of chronic kidney disease (CKD), anaemia is associated with poorer: quality of life, exercise tolerance, mental agility, renal and cardiac function; increased hospitalization and reduced survival on dialysis [1–3]. The development of erythropoiesis-stimulating agents (ESAs) has made anaemia a central part of the management of patients with CKD stages III–V [4–6]. Following successful renal transplantation, some correction of anaemia occurs via endogenous production of ESA from the engrafted kidney but a significant proportion, about one-third of the subjects, remain anaemic [7–9]. Post-transplantation anaemia (PTA) is important as the commonest cause of graft loss is death with a functioning graft, mostly due to an excess of cardiovascular disease, and anaemia is a well-recognized and potent cardiovascular risk factor.
Both ‘early’ and ‘late’ PTA have been identified in this context and the distinction is important in identifying aetiological causes. ‘Early’ PTA refers to anaemia persisting, or arising relatively soon after engraftment. Relevant potential aetiological factors include iron deficiency, infectious agents, donor age, prophylactic and immunosuppressive therapy. ‘Late’ PTA is associated with the decline in renal function observed in the context of chronic allograft nephropathy or recurrent renal pathology [7,10].
Data from studies in children suggest that the prevalence of anaemia is even higher among this population and can affect up to 60% of patients [11,12], but large series are absent from the literature.
The purpose of this study was to determine the prevalence of anaemia in a single-centre population of engrafted adult and paediatric patients and to examine the use of recombinant erythropoietin (EPO) in the cohort of patients with PTA. Using this large clinical cohort, the correlation between the estimated glomerular filtration rate (eGFR), iron indices and the use of immunosuppressants to the prevalence of anaemia was investigated.
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Subjects
All adult and paediatric patients with functioning renal transplants (single or in combination with a pancreatic graft) more than 3 months post-engraftment and attending renal transplant outpatients at Guy's Hospital, London as of 31 December 2004 were identified. Organ transplantation started in adults at Guy's Hospital in 1967—over 2200 transplant operations have been performed to date. Maintenance immunosuppression was prednisolone and azathioprine until 1984, when cyclosporine A was added. Tacrolimus was used increasingly from 1996. Azathioprine was replaced by mycophenolate mofetil (MMF) in 2002. Mycophenolate from 2000 and sirolimus from 2002 were used to reduce calcineurin exposure.
Only patients with a valid haemoglobin value and creatinine in the period 1 September–31 December 2004 were included in the analysis. Paediatric patients were defined as those under the age of 18 (and were cared for by paediatric nephrologists). Patients’ notes and electronic patient records were obtained and a detailed cross-sectional clinical and biochemical database was constructed. Data values included age, gender, aetiology of underlying renal disease, date of engraftment, time out from transplantation (months), haemoglobin (g/dl), haematinics, serum creatinine (µmol/l), immunosuppression and use of angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARB).
Statistical analysis
The database was constructed on Microsoft Excel 2002 (Microsoft Corporation). A statistical analysis was carried out using Microsoft Excel 2002 and StatView for Windows 1999 (SAS Institute Inc). The eGFR (ml/min) was calculated using the modification of diet in renal disease (MDRD) formula in adults (without correction for ethnicity as ethnic data was not available for many subjects) and the Schwartz formula in children. Anaemia was defined as haemoglobin of <13 g/dl in adult males, <12 g/dl in adult females or <11 g/dl in children of either gender. Severe anaemia was defined as haemoglobin of <10 g/dl. All patients who were on treatment with an ESA were classified as anaemic, irrespective of haemoglobin.
Descriptive statistics were presented as means±SD. Comparisons of continuous variables were made using two-tailed t-tests (assuming unequal variance). For the comparison of frequencies in two nominal variables (e.g. subjects on ACE inhibitors and prevalence of anaemia), a two-group chi-square test was used and Fisher's exact P-value was calculated.
Univariate analyses were carried out using Pearson's correlation coefficients and Fisher's r to z-test was used for determination of significance. For multiple regression analysis, a model firstly incorporating haemoglobin as the dependent variable and age, female gender, eGFR, ferritin and C-reactive protein (CRP) as independent variables was examined. The model was then expanded to include further the independent variables of therapy with MMF, sirolimus, ACEI/ARB and post-transplantation diabetes mellitus. In all cases, P-values <0.05 were taken as statistically significant.
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Results |
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Population demographics
A total of 878 adults (547 male) and 73 children (48 male) with functioning transplants who met the inclusion criteria were identified. The population demographics are summarized in Table 1. The mean haemoglobin in adults was 12.9±1.6 g/dl (13.3±1.6 and 12.2±1.4 g/dl, respectively for men and women, P<0.0001) and 11.8±1.4 g/dl in children (11.7±1.3 and 12.0±1.5 g/dl in boys and girls, respectively, P = NS). The prevalence of anaemia in adults was 398 from 878 subjects (45.3% overall, 44.2% in males and 47.1% among females), including 16 patients who were on EPO but who had haemoglobin values above the threshold for anaemia. About 3.6% of adults (32 individuals) met the criteria for severe anaemia. Among anaemic adult males, the mean haemoglobin was 11.8±1 g/dl while anaemic adult females had a slightly lower haemoglobin of 11.2±1.0 g/dl (P<0.0001). In children, the prevalence of anaemia was quantitatively lower at 22% overall (16 from 73 individuals) with a lower prevalence among females than males (16 vs 25%). Six children (8.2%) had severe anaemia. The mean haemoglobin among children with anaemia was 10.0±0.9 g/dl in boys and 9.5±1.5 g/dl in girls (the numbers in children were too small to permit further analysis).
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Only one child was on recombinant EPO while there were 68 adults being treated with this drug. Sixteen of these adult patients had haemoglobin levels above the threshold for anaemia.
Determinants of haemoglobin
In both adult and paediatric subjects, haemoglobin correlated significantly with eGFR. (Pearson correlation coefficients were 0.33 and 0.29, respectively; P<0.0001 for both).
Serum levels of vitamin B12 and folate were available for 348 and 344 adults, respectively. Only one paediatric patient had had a B12 level measured and none had a serum folate. Mean serum B12 for adult subjects was 375±196 (ng/l) with a slightly higher value in anaemic as compared with non-anaemic subjects (397±215 vs 340±154 ng/l, P<0.01). Similarly, the mean serum folate was 8.7±10.1 µg/l with no differerence between those who had PTA and those who did not (8.5±5.5 vs 8.9±15.0 µg/l, P = NS).
For the adults, ferritin values were available in 527 cases. In 248 cases, the ferritin value was <100 µg/l (47%). Mean serum ferritin was 204±353 µg/l in adults. For the children, ferritin values were available in 71 cases. Ferritin values <100 µg/l were seen in 57 cases (80%). The mean value for ferritin was 79±93 µg/l in children.
Among adults, ferritin levels were higher among those with anaemia than those without (238±433 vs 164±218 µg/l, P<0.05). The same pattern was observed in children, but did not reach statistical significance (113±132 vs 69±77 µg/l, P = NS).
CRP levels were available in 704 adult subjects of whom 244 had undetectable levels. Mean CRP was 7.5±10.8 µg/l overall. There was no difference between the levels of CRP between anaemic and non-anaemic adults [8.1±12.3 (n = 325) vs 7.1±9.3 (n = 379) µg/l, P = NS]. There was no correlation between haemoglobin levels and CRP overall (R = –0.03, P = NS) or between CRP and haemoglobin in anaemic (R = –0.007, P = NS) and non-anaemic (R = 0.01, P = NS) patients when considered separately. There was only a weak correlation between ferritin levels and CRP overall (R = 0.1, P = NS) and between CRP and ferritin in anaemic (R = 0.12, P = NS) and non-anaemic subjects (R = 0.05, P = NS).
In children, data on CRP were available for 33 subjects. Mean CRP was 8.4±6.0 µg/l. There was no difference between CRP values in anaemic vs non-anaemic subjects [6.8±4.4 (n = 11) vs 9.2±6.5 (n = 22), P = NS]. CRP showed no correlation with haemoglobin in paediatric renal transplant recipients (R = 0.06, P = NS). There were not enough subjects to split the correlation analysis by the presence or absence of anaemia. Similarly, no correlation between CRP and ferritin levels was observed (R = –0.04, P = NS) in children.
Clinical information regarding post-transplant diabetes mellitus (PTDM) was available in 709 adults and in none of the childhood cohort. In adults, 46 subjects (6.5%) had PTDM of whom 21 (46%) had PTA and 25 (54%) did not. The numbers were too small for further analysis.
Immunosuppression and other drugs
A total of 260 adults were on MMF and 45 on sirolimus. Of these, 152 (58%) and 26 (58%), respectively, were anaemic. Eight adults were taking a combination of MMF and sirolimus and 50% of them had evidence of anaemia. Patients on MMF or sirolimus had significantly lower eGFRs than the patients who were not on these drugs (43.5±16.7 vs 51.8±20.9 ml/min, P<0.0001 for MMF and 40.6±22.3 vs 49.7±19.9 ml/min, P<0.005 for sirolimus), but did not differ in other characteristics with patients not on MMF and sirolimus. The correlation between eGFR and haemoglobin was the same in patients being treated with MMF as those not being treated with MMF (R = 0.30, P<0.0001). Correlation between eGFR and haemoglobin did not reach statistical significance in the sirolimus-treated subjects (R = 0.2, P = 0.2), but small numbers were involved in this analysis.
In children, 23 subjects were taking MMF, 11 were taking sirolimus and three were on a combination of both. Of these, five (22%), six (55%) and two (67%) had anaemia, respectively. The numbers were too small for further analysis.
With regards to ACEI or ARB, data were available in 745 adult subjects. Of these, 248 (33%) were being treated with either an ACEI or ARB. The eGFR was lower in those subjects who were on an ACEI/ARB (46.5±18.8 vs 51.1±20.9 ml/min, P<0.005). Although the mean haemoglobin values were very similar in the ACEI/ARB-treated and non-treated groups (12.7±1.6 vs 12.9±1.6 g/dl, P = NS), the prevalence of anaemia was higher in the group treated with ACEI/ARB (50 vs 40.6%, P<0.05). In children, 10 patients (14%) were on these drugs, five of whom were anaemic. Again, further statistical analysis was not carried out in the paediatric group due to small numbers.
Multiple regression analysis
A multiple regression analysis was carried out in all 878 adult subjects. Haemoglobin was taken as the dependent variable and the independent variables used in this model were age, gender, eGFR, ferritin and CRP. The model predicted 19% (R = 0.44) of the variance in haemoglobin on the basis of these factors (P<0.0001). The eGFR (standard coefficient 0.27, P<0.0001) and female gender (standard coefficient –0.27, P<0.0001) were the strongest predictors of haemoglobin. Serum ferritin (standard coefficient –0.12, P<0.05) and age (standard coefficient 0.17, P<0.0005) were also independent predictors while CRP was not (Table 2).
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When therapy with MMF, sirolimus, ACEI/ARB and PTDM were added to the model, the model predicted 20% of the variance in haemoglobin (R = 0.45, P<0.0001) and the same variables as before, namely eGFR, gender, age and serum ferritin remained independent predictors of haemoglobin whereas drug therapy and diabetes did not (Table 3).
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Discussion |
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This investigation was a cross-sectional observational study of a large population of active adult and paediatric transplant recipients from a single transplantation centre. This is the largest single-centre study reported and the only one to compare adults and children within the same institution, with the same surgical and immunosuppressive protocols. The main findings were that there is a high prevalence of anaemia among the transplant population, reaching almost 45% in adults and 25% in children. These figures are in keeping with the previously published work of others [7,13], most notably the TRansplant European Survey on Anaemia Management (TRESAM) which was a questionnaire-based survey of 72 transplant centres in 16 European countries involving 4263 adult patients [7]. They reported a 38.6% prevalence of anaemia (defined according to the WHO criteria). In their population, the prevalence of severe anaemia was 8.5% which compares with 3.6% in the present study cohort. Among paediatric patients, the current report generally shows a lower incidence of PTA than previously published, notably the cross-sectional analysis of Kausman et al. [12] in 50 paediatric transplant patients, which demonstrated a mean haemoglobin level of 11.0 g/dl (similar to our patients) but a higher prevalence of anaemia at 60%.
This represents a significant disease burden. Direct comparisons between the adult and paediatric populations are difficult to make beyond the main description as these are two very different populations. The mean time post-engraftment was 8 years for adults and 5 years for children, respectively, so overall the data are more representative of ‘late’ rather than ‘early’ PTA. The EPO deficiency in the context of transplant dysfunction is likely to be playing a significant part in the anaemia. The demonstration, as expected [14], of a strong correlation between haemoglobin levels with eGFR in both adult and paediatric cohorts, using both univariate and multivariate analyses, lends credence to this theory—as endogenous allograft-derived production of EPO would decline with worsening transplant function. In fact, the findings point to graft function (eGFR) as being by far the most potent predictor of haemoglobin in this population.
Despite this, few patients were on ESA therapies. This contrasts with the high prevalence of anaemia. About 75% of patients on ESA therapies remained anaemic. The TRESAM group also showed that only 17.8% of their transplant recipients were treated with EPO, again in contrast to the high prevalence of anaemia [7]. There are no separate guidelines for anaemia treatment in adult or paediatric transplantation practice.
With regards to iron indices (reported in the majority of our subjects), our findings show that this was not a major correlate of haemoglobin values; however, relative iron-deficiency—as defined by a ferritin value <100 µg/l was common in adults and nearly ubiquitous in children. This is a useful observation—one of the limitations of some previous studies was the paucity of even the most basic assessment of iron levels despite a high prevalence of anaemia [13]. Previous reports have indicated that iron deficiency is a common finding (34%) in paediatric transplant recipients [12]. While this was also a frequent feature in this cohort, serum levels of ferritin were lower in the paediatric cohort than with their adult counterparts. Nevertheless, ferritin levels were negatively predictive of the haemoglobin level in multiple regression analyses, probably representing targeted iron therapy in subjects who were found to be anaemic. One needs to be cautious not to over-interpret this observation, however, as the serum ferritin level is the only marker of iron status and subject to other influences [15,16].
A previous publication on small numbers of adult transplant recipients suggested that deficiency of folate and B12 is common among anaemic subjects [17]. The present, larger study does not support this. Indeed, levels of vitamin B12 were on average higher amongst the anaemic cohort.
The use of MMF and sirolimus as immunosuppressants seems to be associated with the relatively high prevalence of anaemia in both cohorts. It is clear in clinical practice that the use of MMF is associated with the suppression of all bone marrow cell lines. In the tricontinental MMF study, leucopaenia, anaemia and thrombocytopaenia were reported in 13.9, 7.3 and 6.1% of patients receiving 2 gm MMF/day, and 20, 15 and 5.6% of patients receiving 3 gm/day [18]. In contrast to this, however, Wang et al.'s [19] article presented a meta-analysis of 20 trials containing 6387 subjects on MMF, and found that there were no statistically significant differences in the prevalence or odds ratio of developing anaemia comparing subjects on 2 3 gm/day of MMF with those on a dose of Azathioprine. The TRESAM survey [7] showed a significantly lower Hb for patients on any immunosuppressive drug combination that included MMF (Hb 13.1±2.0 g/dl vs 13.4±2.1 g/dl, P<0.05). This difference was small, and may in part be explained by lower GFR. Similarly, an effect of sirolimus on erythrocyte production has been reported, and this correlates with the drug dose and blood level. In particular, the combination of sirolimus and MMF is clearly very potent in causing bone marrow suppression [20]—Kreis et al. [21] reported a 43% incidence of anaemia in patients on sirolimus and MMF compared with 29% for patients on cyclosporine and MMF.
In our centre, MMF has been used primarily for the limitation of the calcineurin inhibitor (CNI) used in the context of chronic allograft nephropathy (CAN) [22] and only since 2002 as primary immunosuppression for renal transplantation. The majority of subjects on MMF in this study, therefore, were being treated with MMF for CAN. Sirolimus, likewise, was used almost exclusively to permit dose reduction and then withdrawal of CNIs. Therefore, it is not surprising that the patients on MMF and patients on sirolimus in this study had on average a lower eGFR than those not on MMF. It is likely, therefore, that the apparent link with anaemia between MMF and sirolimus is due to the presence of alternative pathology (CAN) and pooper graft function. This is borne out by the multiple regression analysis which demonstrates that neither MMF nor sirolimus therapy was a predictor of haemoglobin in this subject population.
With regards to ACEI/ARB, in the general population there is evidence that these drugs do have a modest population effect in reducing haematocrit—indeed these drugs are now the main medical management of post-transplantation polycythaemia. In the TRESAM survey, there were 25.9% of patients on ACE inhibitors and 10.3% of patients on ARBs [7]. There was no difference between the ACEI/ARB-treated or naïve cohorts in terms of haemoglobin or anaemia prevalence. Similarly, losaratan therapy has previously been reported as having no effect on haemoglobin levels in renal transplant recipients [23]. The present large cohort study did not suggest, despite a lower GFR, that the use of ACE inhibition or ARB blockade had any marked effect on anaemia prevalence.
As a caveat to the above observations, it is important to point out a potential confounder—that it is very possible for patients to develop anaemia in the post-transplantation setting while having good graft function as a result of an interplay of marrow suppressant immunosuppression, such as MMF and sirolimus, and cardio/renoprotective drugs such as ACEI/ARB. An additional limitation of this study is its cross-sectional nature. Although useful as a means of hypothesis generation and pattern recognition, it is critically a ‘snapshot’ view of the populations under study.
Overall, this study has presented data from large cohorts of adult and paediatric renal allograft recipients from one transplantation centre. Using the WHO criteria, there is a high point-prevalence of anaemia within this population. Nevertheless, treatment with ESA therapy was rare. The predictors of anaemia in this study cohort were found to be age, female sex, graft function (eGFR) and, to a more minor extent, serum ferritin. Acute phase reactions, as measured by CRP, therapy with MMF, sirolimus or ACEI/ARB and PTDM were not predictive of post-transplant haemoglobin. This study should form the basis for a prospective investigation of patients with renal transplants to determine the predictors of anaemia in the early and late post-engraftment period and the effects of anaemia correction on outcome.
Conflict of interest statement. B.A. and D.G. have received travel grants from Roche and D.G. has given renumerated lectures on behalf of Roche and Amgen.
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Accepted in revised form: 24. 2.06
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