Departments of Medicine and 1 Surgery, University of Wisconsin Medical School, Madison, WI 53792, USA
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Abstract |
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Methods. We evaluated 166 individuals who initiated erythropoietin therapy after at least 18 days of transplant function. One hundred and nine individuals received erythropoietin between days 18 and 294 of transplant function (group 1-early epoietin alfa) while 57 individuals received erythropoietin on or after day 294 of transplant function (group 2-late epoietin alfa). The slope of serum creatinine (Scr) (slope Scr) prior to and following the start of erythropoietin therapy and calculated glomerular filtration rates (GFR) were used to assess renal function over time.
Results. The average haematocrit rose 6.6% in group 1 patients and 2.1% in group 2 patients during the first 100 days of erythropoietin therapy. The slope Scr was not significantly altered in group 1 patients. However, for group 2 individuals who continued to have graft function (n=35), the
slope Scr became negative during erythropoietin treatment. This indicated a deceleration in the rate of loss of renal function (day 200
slope Scr -0.0033, P=0.00091; day 300
slope Scr -0.0014, P=0.05; day 400
slope Scr -0.0066, N.S., P=0.066). GFR remained stable in both cohorts. Finally, group 2-late epoietin alfa patients treated with erythropoietin demonstrated a marked trend towards longer graft survival than a group of similar control patients (N.S., P=0.064).
Conclusions. The data in a group of renal transplant recipients with chronic allograft dysfunction reinforce data from the CKD realm suggesting that erythropoietin may be of benefit in slowing the rate of loss of function over time. However, this renal response is not evident in all patients. Prospective studies of erythropoietin or erythropoietin-like medications are warranted in this population to better discriminate those who may respond well to administration of these drugs.
Keywords: anaemia; erythropoietin; kidney transplantation
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Introduction |
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These observations prompted additional investigations using erythropoietin in CKD patients. Data now suggest that recombinant erythropoietin therapy may actually retard progression of CKD [5,6]. Transplant recipients with chronic allograft nephropathy (CAN) or other forms of chronic transplant dysfunction could respond in a similar manner when treated with erythropoietin. However, there is reason to question whether erythropoietin would be effective in such individuals. The transplant setting, by virtue of its inherent immunologic disparities, may trigger acute rejection episodes, and induce erythropoietin resistance. Chronic inflammation and haemolysis may exacerbate this state [7]. Finally, while erythropoietin appears to be safe following renal transplantation [8,9], its use in the early post-transplant period has not been associated with improvements in renal function.
The increasing numbers of individuals with CAN and their clinical congruency to CKD suggests, however, that erythropoietin may be beneficial in correcting anaemia late after renal transplantation [1013]. Such an effect could also lead to improvements in renal function akin to those seen in CKD patients. Therefore, we retrospectively evaluated changes in renal function prior to and subsequent to the initiation of erythropoietin in a cohort of renal transplant recipients with chronic transplant dysfunction.
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Patients and methods |
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Clinical and demographic variables were abstracted from the database. Demographic variables included race, age, and cause of end-stage renal disease (ESRD) (Table 1). Standard laboratory parameters were incorporated into the data analysis. Individual patients at our centre have three times weekly laboratory testing during the first month post-transplant. During the second and third months, they have two times weekly or weekly laboratory testing. This is tapered to monthly laboratory testing following that period. Haematocrit values were used for assessment of anaemia treatment as haemoglobin values were obtained with variable frequency (not simultaneous with haematocrit determinations) and were available for only 45% of all of the individuals. Lipid values are recorded every 3 months when possible. Blood pressure measurements obtained at clinic visits were used for assessment of mean systolic and diastolic blood pressure values. Glomerular filtration rates (GFR) were calculated using the method of Nankivell et al. [14].
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A control group of transplant recipients were also culled from the database. These were age- and gender-matched individuals transplanted within 3 years of the erythropoietin-treated cohort. Each carried a diagnosis of biopsy-proven CAN. These individuals did not receive erythropoietin during their post-transplant course. Renal function was assessed as above.
Definitions
Iron deficiency was defined as either documentation of serum iron levels <20 µg/dl, a total iron binding capacity >200 µg/dl, a transferrin saturation <20%, or a serum ferritin <100 ng/ml. Proteinuria was defined as 2+ on urinary dipstick testing. Urinalyses were obtained at all scheduled clinic visits. Quantitative urinary protein excretion values were obtained for the majority of these patients, but because they were not uniformly performed for each patient after documenting dipstick-positive proteinuria, the dipstick testing was used as the variable for evaluation. Acute rejection was defined as biopsy-proven acute rejection of the renal allograft. Renal graft loss was defined as loss of the transplanted kidney. Duration of erythropoietin therapy was defined as treatment until renal graft loss or documented discontinuation of the medication.
Statistical analysis
Comparisons between treatment periods (prior to and following institution of erythropoietin treatment) were analysed by 2 and Student's t-test.
The effect of erythropoietin treatment on renal function was analysed using general linear mixed modelling of the change in slope of serum creatinine (Scr), beginning 100 days prior to initiation of erythropoietin treatment. The change in slope of Scr from this time point until the initiation of erythropoietin therapy was then compared with other time frames following the implementation of erythropoietin therapy with day 0 being the day treatment started and other days defined as day +50, day +100, day +200, day +300, and day +400. Repeated measures analysis of variance was used to examine the change in creatinine slopes over time. Examination of the residuals suggested it was appropriate to model the within-subject error structure as first-order autoregressive, weighted by the inter-measurement time. Estimation was performed using SAS PROC MIXED [16].
Graft survival curves comparing group 2-late epoietin alfa treatment and control patients were generated according to KaplanMeier methodology as described previously [17]. The equality of the survivor function between the two treatment groups was tested using the log-rank test. All analyses were performed using SAS statistical software (SAS Institute, Inc., Cary, NC). Data are reported as mean±standard deviation. A P value 0.05 was considered significant.
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Results |
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Group 1-early epoietin alfa patients
These were individuals treated between days 18 and 294 of transplant function. Their mean age was 44.1 years. Slightly more than half underwent cadaveric renal transplantation (n=57). Diabetes mellitus (type 1 and type 2) accounted for ESRD in 30 of these individuals. All of these individuals were maintained on calcineurin inhibitors and anti-proliferative agents during erythropoietin treatment. Twenty-six of these individuals (23.8%) received angiotensin receptor blockers (ARBs) or angiotensin converting enzyme inhibitors (ACE-I) during erythropoietin treatment.
Group 2-late epoietin alfa patients
These were the individuals treated on or after day 294 of transplant function. This group demonstrated the greatest change in renal function from baseline based on differences between discharge Scr and Scr at initiation of erythropoietin therapy. Their mean age was 39.4±13.9 years. Nearly half underwent cadaveric renal transplantation (n=27). Diabetes mellitus (type 1 and type 2) (n=18) and hypertension (n=8) were the most common causes of ESRD in this group of patients. The number of transplants was evenly distributed during the years of the study analysis (1994, 10; 1995, 12; 1996, 13; 1997, 13; 1998, 6; 1999, 3).
All of these individuals were on calcineurin inhibitors at the start of their erythropoietin treatment (cyclosporine A, n=46; tacrolimus, n=11). Twenty-seven patients (47.4%) discontinued calcineurin inhibitor therapy by day 50 of erythropoietin therapy. By day 100 of erythropoietin therapy, 46 patients (80.7%) in this group had discontinued calcineurin inhibitors.
There was a slight increase in systolic (pre, 146±9 mmHg; therapy, 151±7 mmHg; P=0.046) and diastolic (pre, 88±7 mmHg; therapy, 91±6 mmHg; N.S., P=0.053) blood pressure following the initiation of erythropoietin therapy. However, there was no significant difference in the use of ACE-I or ARBs prior to or following the initiation of erythropoietin therapy (ACE-I pre, n=14; therapy, n=16; ARBs pre, n=20; therapy, n=17).
Anaemia and erythropoietin treatment
Group 1-early epoietin alfa patients
Erythropoietin treatment was initiated on day 35±17 of transplant function. Average haematocrit at the start of erythropoietin therapy was 27.3±2.9%. Seventy-nine individuals (72.4%) met one of the criteria defining iron deficiency at the start of erythropoietin therapy. The average dose of erythropoietin was 9113±3755 units weekly, given s.c. The average duration of erythropoietin therapy was 72±79 days. The response to erythropoietin was readily evident with an increase in haematocrit to 33.9±1.8% by day 100 of therapy (Figure 1A).
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Group 2-late epoietin alfa patients
Erythropoietin treatment was initiated on day 1070±544 of transplant function. Average haematocrit at the start of erythropoietin therapy was 30.6±1.2%. Twenty-six individuals (45.6%) met one of the criteria defining iron deficiency at the start of erythropoietin therapy. The average dose of erythropoietin was 9689±2500 units weekly, given s.c. The average duration of erythropoietin therapy was 206±197 days. The response to the erythropoietin was manifested by an increase in haematocrit to 32.7±1.4% by day 100 of therapy (Figure 1B).
Renal function during erythropoietin treatment
Group 1-early epoietin alfa patients
Average Scr at initiation of erythropoietin therapy was 1.46±0.44 mg/dl (N.S. vs discharge Scr). This remained stable through day 300 of transplant function (day 300 Scr, 1.53±0.57 mg/dl; N.S. vs discharge Scr).
Average GFR was 72.2±21.8 ml/min at the initiation of erythropoietin therapy. This remained stable at 73.1±19.9 ml/min on day 100 of treatment and 69.6±21.1 ml/min on day 300 of transplant function (Figure 2) (N.S. vs initiation of treatment).
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None of these individuals sustained a graft loss during this time period. Twenty-three patients (21.1%) were treated for biopsy-proven acute cellular rejection during this time period. This rate of acute rejection is slightly less than the rate of acute cellular rejection reported for our kidney and SPK transplant population in general during the first post-transplant year [18,19].
Group 2-late epoietin alfa patients
Average Scr for this group of individuals at initiation of erythropoietin therapy was 3.1±1.8 mg/dl. This declined to 2.92±1.6 mg/dl on day 100 of treatment and declined even further to 2.62±1.6 mg/dl on day 300 of therapy.
Average GFR was 27.6±14.2 ml/min at the initiation of erythropoietin therapy. This remained stable at 29.3±11.7 ml/min on day 100 of treatment and increased over time to 30.3±14.1 ml/min (Figure 2) (N.S. vs initiation of treatment).
The slope Scr was negative for all patients who maintained graft function during erythropoietin therapy vs 100 days prior to initiation of erythropoietin therapy (Table 2
). This suggested a deceleration in the loss of renal function during the treatment time period.
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Notably, the rate of graft loss in the group 2-late epoietin alfa treatment group tended to be better than that evident in cohort of similar patients (controls; see Table 1) (Figure 3
) although it did not reach statistical significance (N.S., P=0.064). The control group of patients had a mean GFR of 25.2±15.7 ml/min at the time of documenting CAN. This was not significantly different from the GFR in group 2-late epoietin alfa patients (N.S.). Control patients were not treated with erythropoietin, despite the presence of anaemia at 200 days prior to graft loss (average haematocrit: 25.3±3.3%). Twenty-three individuals in the control group cohort were treated with ACE-I or ARB at some point during their post-transplant course and the majority of these individuals (n=36; 69.2%) were also off of calcineurin inhibitors during the last year of graft function.
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Discussion |
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Anaemia correction in later post-transplant periods, especially with failing allografts may be very different. Patients will respond to erythropoietin although they may require higher doses than anticipated due to immunosuppressive medications (e.g. azathioprine or mycophenolate mofetil), infection, chronic inflammation, and the use of other medications with potential anaemia-inducing effects (e.g. ACE-I) [19]. The theoretical concern, that erythropoietin could hasten the deterioration of renal function, remains. Alternatively, erythropoietin could actually slow the rate of decline of renal function in this setting by limiting transfusions and consequent antigen sensitization, improving oxygen supply to the graft, or exerting its own immunomodulatory effects [19,21,22].
Erythropoietin in this study readily corrected anaemia at an average dose comparable with its use in the CKD setting. It is interesting that we noted a change in the slope Scr towards a more negative value during erythropoietin therapy. This suggests that overall, declining renal function may have decelerated during erythropoietin treatment. The data comparing the group 2-late epoietin alfa treatment patients and the control patients also suggests that erythropoietin may have a beneficial effect in slowing the rate of decline in graft function. However, it must be recognized that (i) this did not quite reach statistical significance and (ii) the control patient group was retrospectively culled and was, in no way, set up at the outset as a formal comparison group.
It is interesting to speculate that improvements in renal oxygen delivery via increased red blood cell production could have altered renal function over time. This, in turn, could alter intrarenal oxidant stress or by itself, reduce oxidative damage via signalling events generated through renal erythropoietin receptors [23,24]. Erythropoietin also could have affected systemic cytokine concentrations [25] thereby changing the chronic inflammatory milieu in the allograft.
Certain caveats must be considered in evaluating the data. This is a single-centre retrospective analysis with all of the inherent flaws of such a study construct. Haematocrit was used for assessing effectiveness of therapy although it is now apparent that haemoglobin may be a better marker to follow in the context of anaemia management. In addition, the possibility of treatment bias cannot be completely discounted. Patients pre-therapy values served as their own controls in this study. As such, if increasing Scr values were, in part, used to decide if patients should start receiving erythropoietin therapy, some of the decrease in Scr slope might be due to a regression to the mean phenomenon. This can be seen when patients in crisis are successfully treated. The fact that GFR appeared to stabilize in erythropoietin-treated patients (both in group 1-early epoietin alfa and group 2-late epoietin alfa treatment cohorts) somewhat counters the likelihood that the aforementioned regression to the mean effect accounted solely for the lack of noted change in renal function.
Graft failure also may bias the remaining functioning graft population toward stable Scr values. However, other variables, e.g. blood pressure, were not significantly different pre-erythropoietin and during therapy. Moreover, there appeared to be a true trend towards a benefit in terms of graft survival in comparing erythropoietin-treated patients with a group of similar transplant recipients who did not receive erythropoietin. The majority of these patients were off calcineurin inhibitors during the last year of their transplant course, reducing the likelihood those medication changes alone accounted for the changes in graft survival. Therefore, we believe any bias induced by graft failure may have played only a minor role in our findings, although a formal prospective study would be required to address this completely.
It is important to recognize as well that 22 individuals did indeed lose their grafts during the study time period. While many of these individuals may have been destined for such an unfortunate outcome, e.g. those already with a low GFR, it is possible that erythropoietin hastened their graft failure by heretofore-undefined mechanisms. It will be appropriate to examine this possibility in a prospective trial, especially given the fact that erythropoietin can stimulate B-cell proliferation and immunoglobulin production [26] as well as interleukin-2 production [27] in vitro.
The data from a set of transplant recipients reinforce data from the CKD setting that suggest erythropoietin could actually have a beneficial effect in decelerating the rate of loss of renal function, in some patients. Additional salutary effects of erythropoietin in such individuals, e.g. effect on myocardial function, quality of life, also may be present. Unfortunately, the renal response may not be manifest in all kidney and kidney-pancreas transplant patients treated in this manner. Based on such data, prospective studies to examine the immunomodulatory effects of erythropoietin and erythropoietin-like drugs and their effects on renal transplant oxygenation are warranted. These would enable us to better understand the mechanism of renal stabilization evident in some patients and allow us to identify patient subgroups that may respond well to such therapy.
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Acknowledgments |
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Notes |
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References |
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