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Clinical risk factors associated with the post-transplant anemia in kidney transplant patients
Clinical ¡!–[INS][R]–¿r¡!–[/INS]–¿isk ¡!–[INS][F]–¿f¡!–[/INS]–¿actors ¡!–[INS][A]–¿a¡!–[/INS]–¿ssociated with the ¡!–[INS][P]–¿p¡!–[/INS]– ¿ost-¡!–[INS][T]–¿t¡!–[/INS]–¿ransplant ¡!–[INS][A]–¿a¡!–[/INS]–¿nemia in ¡!–[INS][K]–¿k¡!–[/INS]–¿idney ¡!–[INS][T]–¿t¡!–[/INS]–¿ransplant ¡!– [INS][P]–¿p¡!–[/INS]–¿atients Youngil Chang, Tariq Shah, ¡!–[INS][David I]–¿David I.¡!–[/INS]–¿ Min, Jae Wook Yang PII: DOI: Reference:
S0966-3274(16)30069-7 doi: 10.1016/j.trim.2016.07.006 TRIM 1050
To appear in:
Transplant Immunology
Received date: Revised date: Accepted date:
7 April 2016 17 July 2016 29 July 2016
Please cite this article as: Chang Youngil, Shah Tariq, Min ¡!–[INS][David I]–¿David I.¡!–[/INS]–¿, Yang Jae Wook, Clinical ¡!–[INS][R]–¿r¡!–[/INS]–¿isk ¡!–[INS][F]–¿f¡!– [/INS]–¿actors ¡!–[INS][A]–¿a¡!–[/INS]–¿ssociated with the ¡!–[INS][P]–¿p¡!–[/INS]–¿ost¡!–[INS][T]–¿t¡!–[/INS]–¿ransplant ¡!–[INS][A]–¿a¡!–[/INS]–¿nemia in ¡!–[INS][K]–¿k¡!– [/INS]–¿idney ¡!–[INS][T]–¿t¡!–[/INS]–¿ransplant ¡!–[INS][P]–¿p¡!–[/INS]–¿atients, Transplant Immunology (2016), doi: 10.1016/j.trim.2016.07.006
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Clinical Risk Factors Associated with the Post-Transplant Anemia in Kidney
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Transplant Patients
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Youngil Chang1,2,3, Tariq Shah 1,2,3, David I Min1,2,3, Jae Wook Yang1,4
1. Mendez National Institute of Transplantation 2. St Vincent Medical Center, Los Angeles, CA
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3. Western University of Health Sciences, Pomona, CA, 4. Sahmyook University, Seoul, Korea
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Running Title: Clinical risk factors associated with post-transplant anemia
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Keywords: Risk factors, Post-transplant anemia, renal transplantation.
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Type of Manuscript: Rapid Communication
Correspondence: Jae Wook Yang, PharmD, PhD, BCPS Email: [email protected] Tel: 82-2-3399-1607 Fax: 82-2-3399-1617 Mailing address: College of Pharmacy, Sahmyook University, 815 Hwarang-ro, Nowon-gu, Seoul, 01795 South Korea
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Each author’s specific contributions to the work are indicated below.
Tariq Shah: research design, data collection, and patient care
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Youngil Chang: clinical data collection, writing manuscript.
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David I Min: research design, clinical data collection, writing manuscript, statistical analysis
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Jae Wook Yang: research design, clinical data collection, statistical analysis, writing manuscript.
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Each author’s addresses and emails are indicated below.
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Youngil Chang: 2222 Ocean View Avenue, Los Angeles, CA 90057-2757 [email protected]
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Tariq Shah: 2222 Ocean View Avenue, Los Angeles, CA 90057-2757 [email protected]
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David I Min: 309 E. 2nd street, Pomona, CA 91766 [email protected]
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Jae Wook Yang 815 Hwarang-ro, Nowon-gu, Seoul, 01795 South Korea [email protected]
This study has been supported in part by the Mendez National Institute of Transplantation, Los Angeles, California, the College of Pharmacy, Sahmyook University, and Western University of Health Sciences, Pomona, California,
All authors declare no conflicts of interest.
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Abbreviations: African American (AA), albumin (Alb), Angiotensin converting enzyme (ACE),
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Angiotensin converting enzyme inhibitor (ACEI), Angiotensin II receptor blocker (ARB), Calcineurin inhibitor (CNI), Caucasian (CAU), Chronic allograft nephropathy (CAN), Chronic
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kidney disease (CKD), confidence interval (CI), Cyclosporine (CSA), Delayed graft function
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(DGF), post-transplant anemia (PTA), Estimated glomerular filtration rate (eGFR), Hemoglobin (Hgb), Hispanics (HISP), Late post-transplant anemia (LPTA), Middle East Asian (MEA),
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Mycophenolic acids (MPA), Odds ratio (OR), Pacific Islander (PI), Post-transplantation anemia
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(PTA), Renin-angiotensin inhibitor (RAI), Serum concentration of creatinine (Scr), Tacrolimus
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(FK), Thymoglobulin (Thymo), World Health Organization (WHO).
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ABSTRACT
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Background: Anemia is a very common occurrence in post-renal transplant patients. Post-
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transplantation anemia (PTA) is associated with significant graft loss or cardiovascular morbidity. The objective of this study is to identify clinical risk factors associated with anemia after kidney
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transplantation.
Methods: Our retrospective cohort study included a total of 570 renal transplant recipients. For
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the definition of anemia, we adopted “the lower limit of normal for Hgb concentration of blood” proposed by Beutler E and Waalen J [14], which has adjustments for age, gender and ethnicity.
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Post-transplant anemia (PTA) was defined as anemia that arose between 30 and 180 days after
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transplantation. Based on this definition, of the 570 renal transplant recipients, 344 patients (62.1%) experienced PTA. The patients were divided into anemic and non-anemic groups, and a
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total of 20 clinical factors were compared between the two groups. Results: In the univariate analysis, age, race, multiple transplants, delayed graft function (DGF), and use of tacrolimus, sirolimus, thymoglobulin, ganciclovir, ACE inhibitors, and ARBs were associated with PTA. In the multivariate analysis, age (>60 years old, OR = 2.62, p = 0.001), race (OR = 2.54, p = 0.001), and use of sirolimus (OR = 2.01, p = 0.019), antiviral agents (OR = 1.96, p = 0.015), thymoglobulin (OR = 1.86, p = 0.011), and DGF (OR = 2.78, p = 0.001) remained significant. Conclusion: The current results show that undergoing a transplant at age 60 or older, use of sirolimus, antiviral agents, and thymoglobulin are independent clinical risk factors associated with PTA. In terms of ethnicity, AA, MEA, or PI is higher risk for PTA and Hispanic is significantly lower risk for PTA compared to Caucasians. Keywords: Risk factors, post-transplant anemia, renal transplantation. 4
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1. INTRODUCTION
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Immediately after transplantation, pre-existing anemia is generally aggravated by perioperative bleeding. Hemoglobin (Hgb) is expected to reach a normal level as time passes
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via normal production of erythropoietin by the engrafted kidney. However, a large number of
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renal allograft recipients remain anemic [1-4]. As only one kidney is transplanted, kidney function seems to be only partially restored, resulting in an incomplete correction of anemia.
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This post-transplantation anemia (PTA) likely contributes to graft loss [5] or post-transplantation
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cardiovascular events, which are the second most common reason for allograft loss and the most common cause of death in patients with a functioning allograft. Persistent anemia after
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renal transplantation leads to decreases in mental capacity and quality of life [6-10].
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2. OBJECTIVE
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The prevalence of PTA has been shown to be 20-80% [10-13]. However, in contrast to anemia in patients with chronic kidney disease (CKD), PTA has attracted little interest. Generally, the main focus of studies in the transplantation field has been placed on prevention of organ rejection and maintenance of good renal function. We undertook the present study in order to identify clinical factors associated with posttransplant anemia (PTA). In this study, we mainly focused on the clinical risk factors identifiable in the pre-transplant stage and very early post-transplant stage (less than 1 month after transplant) because these factors might be useful for predicting future cases of post-transplant anemia. To the best of our knowledge, this is the first study to compare the prevalence of anemia after renal transplantation among different ethnic groups.
3. MATERIALS AND METHODS 6
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3.1. Subjects and Study Design: This is a retrospective cohort study. We identified a total of 628 adult patients (age >18 years) who received renal transplantation at St. Vincent Medical Center,
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Los Angeles, California, between Jan 1, 2003 and March 31, 2014. Of them, 570 patients (413
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from deceased donors, 157 from living donors) were included in this study. Fifty-eight patients
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who had incomplete clinical data were excluded. The median period of follow-up after transplantation was 2.74 years. This study was approved by the Institutional Review Board for
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the study of human subjects at St. Vincent Medical Center.
3.2. Definition: For the definition of anemia, the WHO definition is widely accepted in general
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population, but it may not be very specific to our population, so we adopted “the lower limit of
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normal for Hgb concentration of blood” proposed by Ernest Beutler and Jill Waalen [14], which has adjustments for age, gender and ethnicity (table 1). Post-transplant anemia (PTA) was
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defined as anemia that arose between 30 and 180 days after transplantation. Hgb levels after the first month were counted because Hgb levels during the first 30 days after transplantation were generally unstable owing to perioperative blood loss and insufficiently mature graft function. There are no clear biological markers for ethnicity, so self-reported definitions of ethnicity were used in this study. Severe anemia was defined as Hgb ≤10g/dL in male and females.
Delayed graft function (DGF): It is defined as the patient who requires dialysis support due to poor kidney function at the first week after kidney transplantation. 3.3 Dependent and Independent Variables: PTA was used as the dependent variable. Age, gender, race, number of transplants, delayed graft function (DGF), baseline hemoglobin (Hgb) level, serum concentration of creatinine (Scr), serum albumin (Alb) concentration, estimated glomerular filtration rate (eGFR by Cockcroft-Galt methiod), and use of angiotensin converting 7
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enzyme inhibitor (ACEI), angiotensin II receptor blocker (ARB), cyclosporine (CSA), tacrolimus (FK), mycophenolic acid (MPA), sirolimus, steroids, thymoglobulin, antiviral agents (ganciclovir,
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valganciclovir), and sulfamethoxazole/trimethoprim (Bactrim®), were taken as independent
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variables.
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were taken immediately prior to transplant surgery.
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3.4 Baseline laboratory values: All baseline laboratory values including Hgb, Scr, Alb and eGFR
3.5 Statistical Analysis: A chi-square test was used to determine the differences between the two
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groups for nominal and categorical data. A t-test was used to determine the differences between the two groups for continuous and numerical data. Logistic regression was conducted to
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generate adjusted odds ratios and 95% confidential intervals to validate the significance of
4. RESULTS
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trends. In all cases, p values of less than 0.05 were considered to be statistically significant.
We included a total of 570 renal transplant patients in this PTA study. Among them, 324 patients developed anemia between 30 (2nd month) and 180 days (6th month) after transplantation. Thus, the prevalence of post-transplant anemia was 62.1% and severe anemia was 8.2%. The incidence of anemia declines gradually from 81% in the first month to 29% in the 6th month as mentioned in the literature [15]. 4.1. Demographic characteristics (age, gender, race, and past transplantation history): The characteristics and prevalence of PTA in the study patients are summarized in Table 2 and Figure 1. Among males, the prevalence of PTA was 63.6%, and among females, it was 54.1% (p = 0.031). African Americans (70.0%), Asians (68.0%), and those of miscellaneous ethnicity 8
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(79.2%), which included mid-west Asians and Pacific Islanders, showed a higher prevalence than did Caucasians (62.5%). However, Hispanics showed a lower prevalence than did
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Caucasians, at 52.6% (p = 0.002, Figure 1).
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There was a significant difference in mean age between the PTA patient group and the
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control group (∆ = 7.09, p < 0.001). The mean ages of PTA patients and control subjects were 52.11 ± 9.64 and 45.02 ± 8.32 years old, respectively. The age distribution between the various
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ethnic groups was fairly homogeneous (table 3).
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In the PTA group, 47 patients (13.7%) received multiple renal transplantations (two times or more). In the control group, 17 patients (7.5%) received multiple renal transplantations (p =
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0.029).
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4.2. Anti-hypertensive medications: Of the PTA patients, 28.5% (n = 98) used angiotensin
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converting enzyme inhibitors (ACEIs). However, of the control patients, only 16.8% (n = 38) used ACEIs (p < 0.001).
Of the PTA patients, 11.6% (n = 40) used angiotensin receptor blockers (ARBs). Of the control patients, only 6.2% (n = 14) used ARBs (p = 0.004). Of the PTA patients, 33.7% (n = 116) used renin-angiotensin inhibitors (RAIs), which include ACEI and ARB. However, of the control patients, only 21.2% (n = 48) used RAIs (p = 0.008). 4.3. Immunosuppressants: Of a total of 570 renal transplant patients, 70.9% (n = 404) were treated with tacrolimus (FK), and 39.6% (n = 226) were treated with cyclosporine (CSA) during the study period. Calcineurin inhibitors were changed from tacrolimus to cyclosporine or vice versa in 60 patients (10.5%). Among patients on FK, the prevalence of PTA was 64.4% (n = 260). The use of FK was 9
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statistically different between the PTA and control groups (p =0.003).
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One hundred twenty three and 47 patients (35.8% and 20.8%) were treated with sirolimus in the
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PTA and control groups, respectively (p = 0.001).
Only 234 (41.1%) out of the 570 patients in this study were treated with thymoglobulin. Of
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them, 71.4% of patients (n=167) developed PTA. However, of the remaining 336 patients who
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were not treated with thymoglobulin, only 52.7% (n = 177) developed PTA (p< 0.001). 4.4. Antiviral therapy: Among a total of 570 renal transplant patients, 10.2% (n = 58) were
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treated with valganciclovir; of them, 72.4% (n = 42) developed PTA. Of the patients who were
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not treated with valganciclovir, 59.0% (n = 302) developed PTA (p = 0.049).
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Two hundred sixty eight patients (47.0%) were treated with ganciclovir; of them, 68.3% (n = 183) developed PTA. Among the patients who were not treated with ganciclovir, 53.3% (n = 161)
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developed PTA (p < 0.001).
A total of 292 patients (51.2%) were treated with valganciclovir and/or ganciclovir; among them, 68.5% (n = 200) developed PTA. Among the patients who were not treated with either valganciclovir or ganciclovir, 51.8% (n = 144) developed PTA (p <0.001). 4.5 Delayed graft function (DGF): DGF is significantly associated with PTA (p < 0.001). In the PTA group, 48.0% (n = 165) of patients had DGF. However, in the control group, only 21.7% (n = 49) experienced DGF. Of the patients with DGF (n = 214), 77.1% (n = 165) had PTA; among transplant patients who did not have DGF (n = 356), only 50.3% (n = 179) had PTA. 4.6.
Other
factors:
Gender
was
marginally
significant
and
CSA,
MPA,
steroids,
sulfamethoxazole/trimethoprim, baseline levels of Hgb, Scr, eGFR, and Alb were not significant factors in this study. A significant priori Hgb differences between races was not detected in 10
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our study.
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4.7. Logistic regression: In multivariate analysis, only age, race, sirolimus, antiviral agents, thymoglobulin, and DGF were found to be significantly different in the multivariate analysis.
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Detailed data was summarized in Table 4.
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5. DISCUSSION
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Anemia is suggested to be a major risk factor for graft loss or cardiovascular events in renal transplant patients [2, 5, 23]. Most previous PTA studies were conducted in European countries,
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and most of the study subjects were Caucasian. In contrast, our study population consists of
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four major U. S. ethnicities. In our study, the prevalence of post-transplant anemia (PTA) was 62.1%, which was slightly higher than the one found by other studies [9-12]. The prevalence of
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PTA in Caucasians was 62.5% which is close to our average prevalence of anemia. However, the prevalence of PTA among African Americans, Pacifica Islanders, and mid-east Asians was higher than the average.
African American ethnicity was identified as a risk factor for PTA in a study by Shibagaki et al. [4], but ethnicity was not considered in other recent studies [1, 2, 18]. In our study, African Americans (AA), mid-east Asians (MEA), and Pacific Islanders (PI) had a higher prevalence of PTA than did other ethnic groups. Asian patients had a moderately higher rate of PTA than did Caucasian patients. However, Hispanics had a significantly lower prevalence of PTA than did Caucasians (Figure 1). It is not clear why Hispanics have lower incidence of PTA, however this seems to be consistent with Hispanic paradox in general population, which indicates lower mortality in Hispanics compared to other ethnic groups [26].
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Age seems to be a risk factor for PTA. A significant difference in mean age between the PTA and control groups was observed (∆ = 7.09 years, p < 0.001). In the cohort study by Shah et al.
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[1], age at transplantation was also reported as a predictor of PTA. However, in a study by
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Radoui et al. [18], mean age at transplantation was less in the PTA group than in the non-
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anemia group.
Among the immunosuppressants studied, tacrolimus (FK), sirolimus, and thymoglobulin were
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significantly associated with PTA in our study. Thymoglobulin is known to be responsible for
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hematologically adverse events, such as leukopenia and thrombocytopenia. However, anemia caused by thymoglobulin is rarely reported. Thymoglobulin is used for transplant recipients with a high risk of acute rejection. Patients who have experienced more episodes of acute rejection,
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and been treated for it, have lower mean Hgb levels [2], which may be the reason why
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thymoglobulin was significantly associated with PTA in our study.
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ACE inhibitors are known to be associated with PTA because these drugs reduce angiotensin II, an erythrocyte growth factor [21]. In our study, the use of ACEIs was greater in the PTA group (p < 0.001).
To our knowledge, none of the previous PTA studies included ganciclovir which is used to prevent CMV infection in renal transplant recipients at risk for CMV infection [22]. Thus far, there is no information on the extent to which ganciclovir contributes to PTA. In our study, ganciclovir was significantly associated with PTA in both the univariate and multivariate analyses. However, the different results in studies regarding drug usage can be the result from different indications to prescribe these drugs. Delayed graft function (DGF) was also significantly associated with PTA. A greater prevalence of PTA (77.1%) was seen among patients who experienced DGF than among patients in the control group (50.3%). Other reported results on the correlation between PTA and 12
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DGF are conflicting, though the number of such studies is limited. For example, in Zheng’s study [24], which included 39 renal transplant recipients (15 PTA patients and 24 non-PTA
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patients), no significant difference was seen in the incidence of DGF or slow graft function
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among those who remained anemic at 6 weeks as compared with those who were not anemic.
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However, in Chhabra’s study [25], DGF was observed more frequently among the patients with PTA than among the non-PTA patient group (p = 0.027). Baseline Hgb, Scr, eGFR, and Alb did
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not significantly influence the prevalence of PTA in our study.
The limitation of this study includes that this is a retrospective study. There may not be
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serum iron, folate, B12 and ferritin levels or other diagnostic data for each patient and we don’t know the exact cause of PTA, although we speculate that majority of PTA is associated with
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poor renal function and erythropoietin deficiency as in chronic renal diseases.
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In conclusion, the results of our study showed that the age of the allograft recipient at
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transplantation, the use of sirolimus, antiviral agents, and thymoglobulin, and incompletely recovered kidney function in the early stage (first week) of renal transplantation (DGF) are independent clinical factors associated with post-transplant anemia. In terms of ethnicity, AA, MEA, or PI is higher risk for PTA and Hispanic is significantly lower risk for PTA compared to Caucasians.
These findings can be applied to predict the risk of post-transplant anemia after further studies.
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References
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1] N. Shah, S. Al-Khoury, B. Afzali, et al., Posttransplantation anemia in adult renal allograft recipients: prevalence and predictors, Transplantation 81(8) ( 2006) 1112.
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2] Y. Vanrenterghem, C. Ponticelli, J.M. Morales, et al., Prevalence and management of anemia
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in renal transplant recipients: a European survey, Am. J. Transplant. 3 (2003) 835. 3] L.W. Moore, S.O. Smith, R.P. Winsett, et al., Factors affecting erythropoietin production and
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correction of anemia in kidney transplant recipients, Clin. Transplant. 8 (1994) 358.
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4] Y. Shibagaki, A. Shetty, Anemia is common after kidney transplantation, especially among African Americans, Nephrol. Dial. Transplant. 19( 2004) 2368. 5] P Schjelderup, DO Dahle, H Holdaas, G MjØen, et al. Anemia is a predictor of graft loss but
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not cardiovascular events and all-cause mortality in renal transplant recipients: follow-up data
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from the ALERT study. Clin Transplant
27 (2013) E636.
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6] C.C. Magee, M. Pascual, Update in renal transplantation, Arch. Intern. Med. 164 (2004)1373. 7] G. Offermann, Immunosuppression for long-term maintenance of renal allograft function, Drugs 64 (2004) 1325.
8] S. Aker, K. Ivens, B. Grabensee, P. Heering, Cardiovascular risk factors and diseases after renal transplantation, Int. Urol. Nephrol. 30(6) (1998) 777. 9] N. Kawada, T. Moriyama, N. Ichimaru, R. Imamura, Negative effects of anemia on quality of life and its improvement by complete correction of anemia by administration of recombinant human erythropoietin in posttransplant patients, Clin. Exp. Nephrol. 13 (2009) 355. 10] C.D. Blosser, R.D. Bloom, Posttransplant anemia in solid organ recipients, Transplant. Rev.; 24 (2010) 89. 11] B. Afzali, S. Al-Khoury, N. Shah, A. Mikhail, Anemia after renal transplantation, Am. J. Kid. Dis. 48(4) (2006) 519. 12] Y. Vanrenterghem, Anemia after kidney transplantation, Transplantation 87(9) (2009) 1265. 14
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13] H. Petrone, M. Arriola, L. Re, F. Taylor. National survey of anemia prevalence after kidney transplantation in Argentina, Transplant. Proc. 42 (2010) 288.
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blood hemoglobin concentration? Blood 107(5) (2006) 1747.
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14] E Beutler and J Waalen, The definition of anemia: what is the lower limit of normal of the
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15] Z Huang, T Song, L Fu, Z Rao, et al. Post-renal transplantation anemia at 12 months: prevalence, risk factors, and impact on clinical outcomes. Int Urol Nephrol. 47(9) (2015) 1577.
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16] L.G. Modelli de Andrade, J.M. Gera Abrao, M.F. Cordeiro Carvalho, Anemia at one year is an independent risk factor of graft survival. Int. Urol. Nephrol. 44 (2012) 263.
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17] M.Z. Molnar, I. Mucsi, I.C. Macdougall, et al., Prevalence and management of anemia in renal transplant recipients; data from ten European centers, Nephron. Clin. Pract . 117(2011)
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c127.
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18] A. Radoui, Z. Skalli, I. Haddiya, et al., Prevalence and predictive factors of anemia after renal transplantation: A Moroccan report, Transplant. Proc.; 42 (2010) 3542.
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19] O. Thaunat, C. Beaumont, L. Chatenoud, et al., Anemia after late introduction of sirolimus may correlate with biochemical evidence of a chronic inflammatory state. Transplantation 2005: 80(9):1212.
20] A. Maiorano, G. Stallone, A. Schena, B. Infante. Sirolimus interferes with iron homeostasis in renal transplant recipients, Transplantation 82 (2006) 908. 21] M. Mrug, T. Stopka, B.A. Julian, J.F. Prchal, J.T. Prchal, Angiotensin II stimulates proliferation of normal early erythroid progenitors, J. Clin. Invest. 100 (1997) 2310. 22] E. Razeghi, A. Hadadi, M. Mansor-Kiaei, M. Molavi, P. Khashayar, G. Pourmand, Clinical manifestation, laboratory findings, and the response of treatment in kidney transplant recipients with CMV infection, Transplant. Proc. 39 (2007) 993. 23] B.L. Kasiske, C. Guijarro, Z.A. Massy, M.R. Wiederkehr, J.Z. Ma. Cardiovascular disease after renal transplantation, J. Am. Soc. Nephrol. 7 (1996) 158. 15
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24] S. Zheng, D.W. Coyne, H. Joist, et al., Iron deficiency anemia and iron losses after renal transplantation, Transpl. Int. 22 (2009) 434.
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25] D. Chhabra, M. Grafals, A.I. Skaro, et al., Impact of Anemia after renal transplantation on
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patient and graft survival and on rate of acute rejection, Clin. J. Am. Soc. Nephrol. 3 (2008)
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1168.
26] Markides, K, Coreil, J. The health of Hispanics in the Southwestern United States: An
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epidemiological paradox. Public Health Reports 101 (1986) 253-265.
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Table 1. Adopted criteria of anemia with adjustment for age, gender and race. AA male
Age(y)
18-59
All other male
All other female
≥60
≥18
18-59
≥60
< 12.7
<11.5
< 13.7
< 13.2
≥18
< 12.2
Table 2: Characteristics of the PTA and control groups.
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Hgb(g/dL) < 12.9
AA female
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race
Non Anemia
N=344(62.1%)
N=226(37.9%) 45.02±8.32
<0.001
90(39.8%)
0.031
57(26.0%)
0.002
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Anemia
P value
year
52.11±9.64
Female
Yes
106(30.8%)
Race
CAU
95(27.2%)
AA
35(10.2%)
15(6.6%)
HISP
142(41.3%)
128(56.6%)
ASN
34(9.9%)
16(7.1%)
Others
38(11.0%)
10(4.4%)
Tx ≥ 2x
47(13.7%)
17(7.5%)
0.029
Yes
98(28.5%)
38(16.8%)
<0.001
Yes
40(11.6%)
14(6.2%)
0.004
Yes
116(33.7%)
48(21.2%)
0.001
CSA
Yes
133(38.7%)
93(41.2%)
0.600
FK
Yes
260(75.6%)
144(63.7%)
0.003
MPA
Yes
294(85.5%)
192(85.0%)
0.904
Sirolimus
Yes
123(35.8%)
47(20.8%)
<0.001
Steroids
Yes
336(97.7%)
224(99.1%)
0.329
Thymoglobulin
Yes
167(48.5%)
67(29.6%)
<0.001
Valganciclovir
Yes
42(12.2%)
16(7.1%)
0.049
ACEI ARB RAIs
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Multiple Tx
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Age
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Yes
183(53.2%)
85(37.6%)
<0.001
Antiviral 2 agents
Yes
200(58.1%)
92(40.7%)
<0.001
Bactrim®
Yes
309(89.8%)
199(88.1%)
DGF
Yes
165(48.0%)
49(21.7%)
Baseline Hb
11.99±1.45
11.74±1.39
Baseline Scr
7.31±2.96
7.08±2.76
0.248
Baseline Alb
3.76±0.84
3.72±0.59
0.408
Baseline eGFR
12.11±9.21
11.55±9.22
0.292
0.583
18
<0.001
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2. Ganciclovir or Valganciclovir
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1. ACEI or ARB
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Ganciclovir
0.201
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Table 3. The age distribution between the ethnic groups. 18-49 y/o
50-64 y/o
65
328
194
48 n
%
26.80
12
25.00
> 0.05
17
8.76
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P value
5
10.42
> 0.05
47.87
91
46.91
22
45.83
> 0.05
28
8.54
18
9.28
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570
4
8.33
> 0.05
27
8.23
16
8.25
5
10.42
> 0.05
total
n
%
n
%
CAU
152
88
26.83
52
AA
50
28
8.54
HISP
270
157
ASIAN
50
OTHER
48
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Race
95% CI
P value
Age
>60 y/o
2.62
1.43-4.11
0.001
Race
AA
2.54
1.39-3.91
0.001
Sirolimus
Yes
2.01
1.36-3.72
0.019
Antiviral
Yes
1.96
1.44-3.64
0.015
Thymo
Yes
1.86
1.16-3.23
0.011
DGF
Yes
2.78
1.56-4.32
0.001
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odds
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range
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variant
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Table 4: Results of binary logistic regression analysis
AA=African American, Thymo = thymoglobulin, DGF = delayed graft function, CI = confidence interval, y/o = years old
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Figure 1:
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Figure legend:
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Figure 1. Gender and ethnicity. Gender did not significantly affect PTA. Even though the
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prevalence of PTA was higher in men, the difference was not statistically significant. African
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Americans, mid-east Asians, and Pacific Islanders had a higher prevalence of PTA than did other ethnic groups. Asian patients had a moderately higher rate of PTA than did Caucasian
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patients. On the other hand, Hispanics were less likely to experience PTA than were Caucasians. (AA = African American, MEA = Middle East Asian, PI = Pacific Islander, CAU = Caucasian,
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HISP = Hispanic)
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Highlights
African Americans (AA), mid-east Asians (MEA), and Pacific Islanders (PI) had a higher prevalence of PTA than did other ethnic groups. Hispanics had a significantly lower prevalence of PTA than did Caucasians.
The age of the allograft recipient at transplantation, the use of sirolimus, antiviral agents,
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and thymoglobulin, and incompletely recovered kidney function in the early stage (first
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week) of renal transplantation (DGF) are independent clinical factors associated with post-
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transplant anemia.
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S0966-3274(16)30069-7 doi: 10.1016/j.trim.2016.07.006 TRIM 1050
To appear in:
Transplant Immunology
Received date: Revised date: Accepted date:
7 April 2016 17 July 2016 29 July 2016
Please cite this article as: Chang Youngil, Shah Tariq, Min ¡!–[INS][David I]–¿David I.¡!–[/INS]–¿, Yang Jae Wook, Clinical ¡!–[INS][R]–¿r¡!–[/INS]–¿isk ¡!–[INS][F]–¿f¡!– [/INS]–¿actors ¡!–[INS][A]–¿a¡!–[/INS]–¿ssociated with the ¡!–[INS][P]–¿p¡!–[/INS]–¿ost¡!–[INS][T]–¿t¡!–[/INS]–¿ransplant ¡!–[INS][A]–¿a¡!–[/INS]–¿nemia in ¡!–[INS][K]–¿k¡!– [/INS]–¿idney ¡!–[INS][T]–¿t¡!–[/INS]–¿ransplant ¡!–[INS][P]–¿p¡!–[/INS]–¿atients, Transplant Immunology (2016), doi: 10.1016/j.trim.2016.07.006
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Clinical Risk Factors Associated with the Post-Transplant Anemia in Kidney
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Transplant Patients
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Youngil Chang1,2,3, Tariq Shah 1,2,3, David I Min1,2,3, Jae Wook Yang1,4
1. Mendez National Institute of Transplantation 2. St Vincent Medical Center, Los Angeles, CA
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3. Western University of Health Sciences, Pomona, CA, 4. Sahmyook University, Seoul, Korea
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Running Title: Clinical risk factors associated with post-transplant anemia
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Keywords: Risk factors, Post-transplant anemia, renal transplantation.
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Type of Manuscript: Rapid Communication
Correspondence: Jae Wook Yang, PharmD, PhD, BCPS Email: [email protected] Tel: 82-2-3399-1607 Fax: 82-2-3399-1617 Mailing address: College of Pharmacy, Sahmyook University, 815 Hwarang-ro, Nowon-gu, Seoul, 01795 South Korea
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Each author’s specific contributions to the work are indicated below.
Tariq Shah: research design, data collection, and patient care
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Youngil Chang: clinical data collection, writing manuscript.
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David I Min: research design, clinical data collection, writing manuscript, statistical analysis
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Jae Wook Yang: research design, clinical data collection, statistical analysis, writing manuscript.
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Each author’s addresses and emails are indicated below.
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Youngil Chang: 2222 Ocean View Avenue, Los Angeles, CA 90057-2757 [email protected]
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Tariq Shah: 2222 Ocean View Avenue, Los Angeles, CA 90057-2757 [email protected]
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David I Min: 309 E. 2nd street, Pomona, CA 91766 [email protected]
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Jae Wook Yang 815 Hwarang-ro, Nowon-gu, Seoul, 01795 South Korea [email protected]
This study has been supported in part by the Mendez National Institute of Transplantation, Los Angeles, California, the College of Pharmacy, Sahmyook University, and Western University of Health Sciences, Pomona, California,
All authors declare no conflicts of interest.
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Abbreviations: African American (AA), albumin (Alb), Angiotensin converting enzyme (ACE),
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Angiotensin converting enzyme inhibitor (ACEI), Angiotensin II receptor blocker (ARB), Calcineurin inhibitor (CNI), Caucasian (CAU), Chronic allograft nephropathy (CAN), Chronic
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kidney disease (CKD), confidence interval (CI), Cyclosporine (CSA), Delayed graft function
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(DGF), post-transplant anemia (PTA), Estimated glomerular filtration rate (eGFR), Hemoglobin (Hgb), Hispanics (HISP), Late post-transplant anemia (LPTA), Middle East Asian (MEA),
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Mycophenolic acids (MPA), Odds ratio (OR), Pacific Islander (PI), Post-transplantation anemia
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(PTA), Renin-angiotensin inhibitor (RAI), Serum concentration of creatinine (Scr), Tacrolimus
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(FK), Thymoglobulin (Thymo), World Health Organization (WHO).
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ABSTRACT
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Background: Anemia is a very common occurrence in post-renal transplant patients. Post-
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transplantation anemia (PTA) is associated with significant graft loss or cardiovascular morbidity. The objective of this study is to identify clinical risk factors associated with anemia after kidney
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transplantation.
Methods: Our retrospective cohort study included a total of 570 renal transplant recipients. For
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the definition of anemia, we adopted “the lower limit of normal for Hgb concentration of blood” proposed by Beutler E and Waalen J [14], which has adjustments for age, gender and ethnicity.
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Post-transplant anemia (PTA) was defined as anemia that arose between 30 and 180 days after
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transplantation. Based on this definition, of the 570 renal transplant recipients, 344 patients (62.1%) experienced PTA. The patients were divided into anemic and non-anemic groups, and a
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total of 20 clinical factors were compared between the two groups. Results: In the univariate analysis, age, race, multiple transplants, delayed graft function (DGF), and use of tacrolimus, sirolimus, thymoglobulin, ganciclovir, ACE inhibitors, and ARBs were associated with PTA. In the multivariate analysis, age (>60 years old, OR = 2.62, p = 0.001), race (OR = 2.54, p = 0.001), and use of sirolimus (OR = 2.01, p = 0.019), antiviral agents (OR = 1.96, p = 0.015), thymoglobulin (OR = 1.86, p = 0.011), and DGF (OR = 2.78, p = 0.001) remained significant. Conclusion: The current results show that undergoing a transplant at age 60 or older, use of sirolimus, antiviral agents, and thymoglobulin are independent clinical risk factors associated with PTA. In terms of ethnicity, AA, MEA, or PI is higher risk for PTA and Hispanic is significantly lower risk for PTA compared to Caucasians. Keywords: Risk factors, post-transplant anemia, renal transplantation. 4
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1. INTRODUCTION
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Immediately after transplantation, pre-existing anemia is generally aggravated by perioperative bleeding. Hemoglobin (Hgb) is expected to reach a normal level as time passes
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via normal production of erythropoietin by the engrafted kidney. However, a large number of
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renal allograft recipients remain anemic [1-4]. As only one kidney is transplanted, kidney function seems to be only partially restored, resulting in an incomplete correction of anemia.
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This post-transplantation anemia (PTA) likely contributes to graft loss [5] or post-transplantation
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cardiovascular events, which are the second most common reason for allograft loss and the most common cause of death in patients with a functioning allograft. Persistent anemia after
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renal transplantation leads to decreases in mental capacity and quality of life [6-10].
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2. OBJECTIVE
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The prevalence of PTA has been shown to be 20-80% [10-13]. However, in contrast to anemia in patients with chronic kidney disease (CKD), PTA has attracted little interest. Generally, the main focus of studies in the transplantation field has been placed on prevention of organ rejection and maintenance of good renal function. We undertook the present study in order to identify clinical factors associated with posttransplant anemia (PTA). In this study, we mainly focused on the clinical risk factors identifiable in the pre-transplant stage and very early post-transplant stage (less than 1 month after transplant) because these factors might be useful for predicting future cases of post-transplant anemia. To the best of our knowledge, this is the first study to compare the prevalence of anemia after renal transplantation among different ethnic groups.
3. MATERIALS AND METHODS 6
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3.1. Subjects and Study Design: This is a retrospective cohort study. We identified a total of 628 adult patients (age >18 years) who received renal transplantation at St. Vincent Medical Center,
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Los Angeles, California, between Jan 1, 2003 and March 31, 2014. Of them, 570 patients (413
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from deceased donors, 157 from living donors) were included in this study. Fifty-eight patients
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who had incomplete clinical data were excluded. The median period of follow-up after transplantation was 2.74 years. This study was approved by the Institutional Review Board for
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the study of human subjects at St. Vincent Medical Center.
3.2. Definition: For the definition of anemia, the WHO definition is widely accepted in general
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population, but it may not be very specific to our population, so we adopted “the lower limit of
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normal for Hgb concentration of blood” proposed by Ernest Beutler and Jill Waalen [14], which has adjustments for age, gender and ethnicity (table 1). Post-transplant anemia (PTA) was
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defined as anemia that arose between 30 and 180 days after transplantation. Hgb levels after the first month were counted because Hgb levels during the first 30 days after transplantation were generally unstable owing to perioperative blood loss and insufficiently mature graft function. There are no clear biological markers for ethnicity, so self-reported definitions of ethnicity were used in this study. Severe anemia was defined as Hgb ≤10g/dL in male and females.
Delayed graft function (DGF): It is defined as the patient who requires dialysis support due to poor kidney function at the first week after kidney transplantation. 3.3 Dependent and Independent Variables: PTA was used as the dependent variable. Age, gender, race, number of transplants, delayed graft function (DGF), baseline hemoglobin (Hgb) level, serum concentration of creatinine (Scr), serum albumin (Alb) concentration, estimated glomerular filtration rate (eGFR by Cockcroft-Galt methiod), and use of angiotensin converting 7
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enzyme inhibitor (ACEI), angiotensin II receptor blocker (ARB), cyclosporine (CSA), tacrolimus (FK), mycophenolic acid (MPA), sirolimus, steroids, thymoglobulin, antiviral agents (ganciclovir,
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valganciclovir), and sulfamethoxazole/trimethoprim (Bactrim®), were taken as independent
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variables.
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were taken immediately prior to transplant surgery.
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3.4 Baseline laboratory values: All baseline laboratory values including Hgb, Scr, Alb and eGFR
3.5 Statistical Analysis: A chi-square test was used to determine the differences between the two
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groups for nominal and categorical data. A t-test was used to determine the differences between the two groups for continuous and numerical data. Logistic regression was conducted to
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generate adjusted odds ratios and 95% confidential intervals to validate the significance of
4. RESULTS
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trends. In all cases, p values of less than 0.05 were considered to be statistically significant.
We included a total of 570 renal transplant patients in this PTA study. Among them, 324 patients developed anemia between 30 (2nd month) and 180 days (6th month) after transplantation. Thus, the prevalence of post-transplant anemia was 62.1% and severe anemia was 8.2%. The incidence of anemia declines gradually from 81% in the first month to 29% in the 6th month as mentioned in the literature [15]. 4.1. Demographic characteristics (age, gender, race, and past transplantation history): The characteristics and prevalence of PTA in the study patients are summarized in Table 2 and Figure 1. Among males, the prevalence of PTA was 63.6%, and among females, it was 54.1% (p = 0.031). African Americans (70.0%), Asians (68.0%), and those of miscellaneous ethnicity 8
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(79.2%), which included mid-west Asians and Pacific Islanders, showed a higher prevalence than did Caucasians (62.5%). However, Hispanics showed a lower prevalence than did
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Caucasians, at 52.6% (p = 0.002, Figure 1).
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There was a significant difference in mean age between the PTA patient group and the
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control group (∆ = 7.09, p < 0.001). The mean ages of PTA patients and control subjects were 52.11 ± 9.64 and 45.02 ± 8.32 years old, respectively. The age distribution between the various
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ethnic groups was fairly homogeneous (table 3).
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In the PTA group, 47 patients (13.7%) received multiple renal transplantations (two times or more). In the control group, 17 patients (7.5%) received multiple renal transplantations (p =
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0.029).
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4.2. Anti-hypertensive medications: Of the PTA patients, 28.5% (n = 98) used angiotensin
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converting enzyme inhibitors (ACEIs). However, of the control patients, only 16.8% (n = 38) used ACEIs (p < 0.001).
Of the PTA patients, 11.6% (n = 40) used angiotensin receptor blockers (ARBs). Of the control patients, only 6.2% (n = 14) used ARBs (p = 0.004). Of the PTA patients, 33.7% (n = 116) used renin-angiotensin inhibitors (RAIs), which include ACEI and ARB. However, of the control patients, only 21.2% (n = 48) used RAIs (p = 0.008). 4.3. Immunosuppressants: Of a total of 570 renal transplant patients, 70.9% (n = 404) were treated with tacrolimus (FK), and 39.6% (n = 226) were treated with cyclosporine (CSA) during the study period. Calcineurin inhibitors were changed from tacrolimus to cyclosporine or vice versa in 60 patients (10.5%). Among patients on FK, the prevalence of PTA was 64.4% (n = 260). The use of FK was 9
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statistically different between the PTA and control groups (p =0.003).
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One hundred twenty three and 47 patients (35.8% and 20.8%) were treated with sirolimus in the
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PTA and control groups, respectively (p = 0.001).
Only 234 (41.1%) out of the 570 patients in this study were treated with thymoglobulin. Of
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them, 71.4% of patients (n=167) developed PTA. However, of the remaining 336 patients who
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were not treated with thymoglobulin, only 52.7% (n = 177) developed PTA (p< 0.001). 4.4. Antiviral therapy: Among a total of 570 renal transplant patients, 10.2% (n = 58) were
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treated with valganciclovir; of them, 72.4% (n = 42) developed PTA. Of the patients who were
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not treated with valganciclovir, 59.0% (n = 302) developed PTA (p = 0.049).
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Two hundred sixty eight patients (47.0%) were treated with ganciclovir; of them, 68.3% (n = 183) developed PTA. Among the patients who were not treated with ganciclovir, 53.3% (n = 161)
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developed PTA (p < 0.001).
A total of 292 patients (51.2%) were treated with valganciclovir and/or ganciclovir; among them, 68.5% (n = 200) developed PTA. Among the patients who were not treated with either valganciclovir or ganciclovir, 51.8% (n = 144) developed PTA (p <0.001). 4.5 Delayed graft function (DGF): DGF is significantly associated with PTA (p < 0.001). In the PTA group, 48.0% (n = 165) of patients had DGF. However, in the control group, only 21.7% (n = 49) experienced DGF. Of the patients with DGF (n = 214), 77.1% (n = 165) had PTA; among transplant patients who did not have DGF (n = 356), only 50.3% (n = 179) had PTA. 4.6.
Other
factors:
Gender
was
marginally
significant
and
CSA,
MPA,
steroids,
sulfamethoxazole/trimethoprim, baseline levels of Hgb, Scr, eGFR, and Alb were not significant factors in this study. A significant priori Hgb differences between races was not detected in 10
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our study.
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4.7. Logistic regression: In multivariate analysis, only age, race, sirolimus, antiviral agents, thymoglobulin, and DGF were found to be significantly different in the multivariate analysis.
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Detailed data was summarized in Table 4.
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5. DISCUSSION
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Anemia is suggested to be a major risk factor for graft loss or cardiovascular events in renal transplant patients [2, 5, 23]. Most previous PTA studies were conducted in European countries,
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and most of the study subjects were Caucasian. In contrast, our study population consists of
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four major U. S. ethnicities. In our study, the prevalence of post-transplant anemia (PTA) was 62.1%, which was slightly higher than the one found by other studies [9-12]. The prevalence of
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PTA in Caucasians was 62.5% which is close to our average prevalence of anemia. However, the prevalence of PTA among African Americans, Pacifica Islanders, and mid-east Asians was higher than the average.
African American ethnicity was identified as a risk factor for PTA in a study by Shibagaki et al. [4], but ethnicity was not considered in other recent studies [1, 2, 18]. In our study, African Americans (AA), mid-east Asians (MEA), and Pacific Islanders (PI) had a higher prevalence of PTA than did other ethnic groups. Asian patients had a moderately higher rate of PTA than did Caucasian patients. However, Hispanics had a significantly lower prevalence of PTA than did Caucasians (Figure 1). It is not clear why Hispanics have lower incidence of PTA, however this seems to be consistent with Hispanic paradox in general population, which indicates lower mortality in Hispanics compared to other ethnic groups [26].
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Age seems to be a risk factor for PTA. A significant difference in mean age between the PTA and control groups was observed (∆ = 7.09 years, p < 0.001). In the cohort study by Shah et al.
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[1], age at transplantation was also reported as a predictor of PTA. However, in a study by
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Radoui et al. [18], mean age at transplantation was less in the PTA group than in the non-
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anemia group.
Among the immunosuppressants studied, tacrolimus (FK), sirolimus, and thymoglobulin were
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significantly associated with PTA in our study. Thymoglobulin is known to be responsible for
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hematologically adverse events, such as leukopenia and thrombocytopenia. However, anemia caused by thymoglobulin is rarely reported. Thymoglobulin is used for transplant recipients with a high risk of acute rejection. Patients who have experienced more episodes of acute rejection,
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and been treated for it, have lower mean Hgb levels [2], which may be the reason why
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thymoglobulin was significantly associated with PTA in our study.
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ACE inhibitors are known to be associated with PTA because these drugs reduce angiotensin II, an erythrocyte growth factor [21]. In our study, the use of ACEIs was greater in the PTA group (p < 0.001).
To our knowledge, none of the previous PTA studies included ganciclovir which is used to prevent CMV infection in renal transplant recipients at risk for CMV infection [22]. Thus far, there is no information on the extent to which ganciclovir contributes to PTA. In our study, ganciclovir was significantly associated with PTA in both the univariate and multivariate analyses. However, the different results in studies regarding drug usage can be the result from different indications to prescribe these drugs. Delayed graft function (DGF) was also significantly associated with PTA. A greater prevalence of PTA (77.1%) was seen among patients who experienced DGF than among patients in the control group (50.3%). Other reported results on the correlation between PTA and 12
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DGF are conflicting, though the number of such studies is limited. For example, in Zheng’s study [24], which included 39 renal transplant recipients (15 PTA patients and 24 non-PTA
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patients), no significant difference was seen in the incidence of DGF or slow graft function
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among those who remained anemic at 6 weeks as compared with those who were not anemic.
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However, in Chhabra’s study [25], DGF was observed more frequently among the patients with PTA than among the non-PTA patient group (p = 0.027). Baseline Hgb, Scr, eGFR, and Alb did
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not significantly influence the prevalence of PTA in our study.
The limitation of this study includes that this is a retrospective study. There may not be
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serum iron, folate, B12 and ferritin levels or other diagnostic data for each patient and we don’t know the exact cause of PTA, although we speculate that majority of PTA is associated with
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poor renal function and erythropoietin deficiency as in chronic renal diseases.
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In conclusion, the results of our study showed that the age of the allograft recipient at
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transplantation, the use of sirolimus, antiviral agents, and thymoglobulin, and incompletely recovered kidney function in the early stage (first week) of renal transplantation (DGF) are independent clinical factors associated with post-transplant anemia. In terms of ethnicity, AA, MEA, or PI is higher risk for PTA and Hispanic is significantly lower risk for PTA compared to Caucasians.
These findings can be applied to predict the risk of post-transplant anemia after further studies.
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References
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1] N. Shah, S. Al-Khoury, B. Afzali, et al., Posttransplantation anemia in adult renal allograft recipients: prevalence and predictors, Transplantation 81(8) ( 2006) 1112.
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2] Y. Vanrenterghem, C. Ponticelli, J.M. Morales, et al., Prevalence and management of anemia
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in renal transplant recipients: a European survey, Am. J. Transplant. 3 (2003) 835. 3] L.W. Moore, S.O. Smith, R.P. Winsett, et al., Factors affecting erythropoietin production and
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correction of anemia in kidney transplant recipients, Clin. Transplant. 8 (1994) 358.
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4] Y. Shibagaki, A. Shetty, Anemia is common after kidney transplantation, especially among African Americans, Nephrol. Dial. Transplant. 19( 2004) 2368. 5] P Schjelderup, DO Dahle, H Holdaas, G MjØen, et al. Anemia is a predictor of graft loss but
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not cardiovascular events and all-cause mortality in renal transplant recipients: follow-up data
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from the ALERT study. Clin Transplant
27 (2013) E636.
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6] C.C. Magee, M. Pascual, Update in renal transplantation, Arch. Intern. Med. 164 (2004)1373. 7] G. Offermann, Immunosuppression for long-term maintenance of renal allograft function, Drugs 64 (2004) 1325.
8] S. Aker, K. Ivens, B. Grabensee, P. Heering, Cardiovascular risk factors and diseases after renal transplantation, Int. Urol. Nephrol. 30(6) (1998) 777. 9] N. Kawada, T. Moriyama, N. Ichimaru, R. Imamura, Negative effects of anemia on quality of life and its improvement by complete correction of anemia by administration of recombinant human erythropoietin in posttransplant patients, Clin. Exp. Nephrol. 13 (2009) 355. 10] C.D. Blosser, R.D. Bloom, Posttransplant anemia in solid organ recipients, Transplant. Rev.; 24 (2010) 89. 11] B. Afzali, S. Al-Khoury, N. Shah, A. Mikhail, Anemia after renal transplantation, Am. J. Kid. Dis. 48(4) (2006) 519. 12] Y. Vanrenterghem, Anemia after kidney transplantation, Transplantation 87(9) (2009) 1265. 14
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13] H. Petrone, M. Arriola, L. Re, F. Taylor. National survey of anemia prevalence after kidney transplantation in Argentina, Transplant. Proc. 42 (2010) 288.
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blood hemoglobin concentration? Blood 107(5) (2006) 1747.
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14] E Beutler and J Waalen, The definition of anemia: what is the lower limit of normal of the
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15] Z Huang, T Song, L Fu, Z Rao, et al. Post-renal transplantation anemia at 12 months: prevalence, risk factors, and impact on clinical outcomes. Int Urol Nephrol. 47(9) (2015) 1577.
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16] L.G. Modelli de Andrade, J.M. Gera Abrao, M.F. Cordeiro Carvalho, Anemia at one year is an independent risk factor of graft survival. Int. Urol. Nephrol. 44 (2012) 263.
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17] M.Z. Molnar, I. Mucsi, I.C. Macdougall, et al., Prevalence and management of anemia in renal transplant recipients; data from ten European centers, Nephron. Clin. Pract . 117(2011)
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c127.
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18] A. Radoui, Z. Skalli, I. Haddiya, et al., Prevalence and predictive factors of anemia after renal transplantation: A Moroccan report, Transplant. Proc.; 42 (2010) 3542.
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19] O. Thaunat, C. Beaumont, L. Chatenoud, et al., Anemia after late introduction of sirolimus may correlate with biochemical evidence of a chronic inflammatory state. Transplantation 2005: 80(9):1212.
20] A. Maiorano, G. Stallone, A. Schena, B. Infante. Sirolimus interferes with iron homeostasis in renal transplant recipients, Transplantation 82 (2006) 908. 21] M. Mrug, T. Stopka, B.A. Julian, J.F. Prchal, J.T. Prchal, Angiotensin II stimulates proliferation of normal early erythroid progenitors, J. Clin. Invest. 100 (1997) 2310. 22] E. Razeghi, A. Hadadi, M. Mansor-Kiaei, M. Molavi, P. Khashayar, G. Pourmand, Clinical manifestation, laboratory findings, and the response of treatment in kidney transplant recipients with CMV infection, Transplant. Proc. 39 (2007) 993. 23] B.L. Kasiske, C. Guijarro, Z.A. Massy, M.R. Wiederkehr, J.Z. Ma. Cardiovascular disease after renal transplantation, J. Am. Soc. Nephrol. 7 (1996) 158. 15
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24] S. Zheng, D.W. Coyne, H. Joist, et al., Iron deficiency anemia and iron losses after renal transplantation, Transpl. Int. 22 (2009) 434.
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25] D. Chhabra, M. Grafals, A.I. Skaro, et al., Impact of Anemia after renal transplantation on
RI
patient and graft survival and on rate of acute rejection, Clin. J. Am. Soc. Nephrol. 3 (2008)
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1168.
26] Markides, K, Coreil, J. The health of Hispanics in the Southwestern United States: An
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epidemiological paradox. Public Health Reports 101 (1986) 253-265.
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Table 1. Adopted criteria of anemia with adjustment for age, gender and race. AA male
Age(y)
18-59
All other male
All other female
≥60
≥18
18-59
≥60
< 12.7
<11.5
< 13.7
< 13.2
≥18
< 12.2
Table 2: Characteristics of the PTA and control groups.
SC
RI
Hgb(g/dL) < 12.9
AA female
PT
race
Non Anemia
N=344(62.1%)
N=226(37.9%) 45.02±8.32
<0.001
90(39.8%)
0.031
57(26.0%)
0.002
NU
Anemia
P value
year
52.11±9.64
Female
Yes
106(30.8%)
Race
CAU
95(27.2%)
AA
35(10.2%)
15(6.6%)
HISP
142(41.3%)
128(56.6%)
ASN
34(9.9%)
16(7.1%)
Others
38(11.0%)
10(4.4%)
Tx ≥ 2x
47(13.7%)
17(7.5%)
0.029
Yes
98(28.5%)
38(16.8%)
<0.001
Yes
40(11.6%)
14(6.2%)
0.004
Yes
116(33.7%)
48(21.2%)
0.001
CSA
Yes
133(38.7%)
93(41.2%)
0.600
FK
Yes
260(75.6%)
144(63.7%)
0.003
MPA
Yes
294(85.5%)
192(85.0%)
0.904
Sirolimus
Yes
123(35.8%)
47(20.8%)
<0.001
Steroids
Yes
336(97.7%)
224(99.1%)
0.329
Thymoglobulin
Yes
167(48.5%)
67(29.6%)
<0.001
Valganciclovir
Yes
42(12.2%)
16(7.1%)
0.049
ACEI ARB RAIs
1
D
TE
AC CE P
Multiple Tx
MA
Age
17
ACCEPTED MANUSCRIPT
Yes
183(53.2%)
85(37.6%)
<0.001
Antiviral 2 agents
Yes
200(58.1%)
92(40.7%)
<0.001
Bactrim®
Yes
309(89.8%)
199(88.1%)
DGF
Yes
165(48.0%)
49(21.7%)
Baseline Hb
11.99±1.45
11.74±1.39
Baseline Scr
7.31±2.96
7.08±2.76
0.248
Baseline Alb
3.76±0.84
3.72±0.59
0.408
Baseline eGFR
12.11±9.21
11.55±9.22
0.292
0.583
18
<0.001
RI
SC
NU
MA
TE
D
2. Ganciclovir or Valganciclovir
AC CE P
1. ACEI or ARB
PT
Ganciclovir
0.201
ACCEPTED MANUSCRIPT
Table 3. The age distribution between the ethnic groups. 18-49 y/o
50-64 y/o
65
328
194
48 n
%
26.80
12
25.00
> 0.05
17
8.76
PT
P value
5
10.42
> 0.05
47.87
91
46.91
22
45.83
> 0.05
28
8.54
18
9.28
RI
570
4
8.33
> 0.05
27
8.23
16
8.25
5
10.42
> 0.05
total
n
%
n
%
CAU
152
88
26.83
52
AA
50
28
8.54
HISP
270
157
ASIAN
50
OTHER
48
NU
SC
Race
95% CI
P value
Age
>60 y/o
2.62
1.43-4.11
0.001
Race
AA
2.54
1.39-3.91
0.001
Sirolimus
Yes
2.01
1.36-3.72
0.019
Antiviral
Yes
1.96
1.44-3.64
0.015
Thymo
Yes
1.86
1.16-3.23
0.011
DGF
Yes
2.78
1.56-4.32
0.001
D
odds
TE
range
AC CE P
variant
MA
Table 4: Results of binary logistic regression analysis
AA=African American, Thymo = thymoglobulin, DGF = delayed graft function, CI = confidence interval, y/o = years old
19
Figure 1:
AC CE P
TE
D
MA
NU
SC
RI
PT
ACCEPTED MANUSCRIPT
20
ACCEPTED MANUSCRIPT
Figure legend:
PT
Figure 1. Gender and ethnicity. Gender did not significantly affect PTA. Even though the
RI
prevalence of PTA was higher in men, the difference was not statistically significant. African
SC
Americans, mid-east Asians, and Pacific Islanders had a higher prevalence of PTA than did other ethnic groups. Asian patients had a moderately higher rate of PTA than did Caucasian
NU
patients. On the other hand, Hispanics were less likely to experience PTA than were Caucasians. (AA = African American, MEA = Middle East Asian, PI = Pacific Islander, CAU = Caucasian,
AC CE P
TE
D
MA
HISP = Hispanic)
21
ACCEPTED MANUSCRIPT
Highlights
African Americans (AA), mid-east Asians (MEA), and Pacific Islanders (PI) had a higher prevalence of PTA than did other ethnic groups. Hispanics had a significantly lower prevalence of PTA than did Caucasians.
The age of the allograft recipient at transplantation, the use of sirolimus, antiviral agents,
PT
RI
and thymoglobulin, and incompletely recovered kidney function in the early stage (first
SC
week) of renal transplantation (DGF) are independent clinical factors associated with post-
AC CE P
TE
D
MA
NU
transplant anemia.
22