|Year : 2021 | Volume
| Issue : 2 | Page : 93-98
Prevalence of posttransplant anemia in patients undergoing renal transplantation at a tertiary care center in Kerala - A prospective observational study
Surabhi Talwar, Rajesh Nair, Sandeep Sreedharan, Anil Mathew, Zachariah Paul, George Kurian
Department of Nephrology, Amrita Institute of Medical Sciences, Kochi, Kerala, India
|Date of Submission||06-May-2020|
|Date of Decision||15-Jul-2020|
|Date of Acceptance||07-Aug-2020|
|Date of Web Publication||30-Jun-2021|
Dr. Rajesh Nair
Department of Nephrology, Amrita Institute of Medical Sciences, Kochi, Kerala
Source of Support: None, Conflict of Interest: None
Background: Studies on posttransplantation anemia (PTA) are scarce. There is a large variability in its prevalence (20%–70%). Research focuses on anemia in early (3–6 months) or late (>6 months) posttransplant period. Little is known about PTA within first 3 months. Aim: The aim of the study was to determine the prevalence and possible associated factors of immediate PTA in patients undergoing renal transplant. Materials and Methods: This was a prospective, observational, single-center study of 30 consecutive patients who underwent live renal allograft transplant. Follow-up period was 3-month posttransplant. Hemoglobin (Hb) was done at 1-week and 1, 2, and 3-month posttransplant. Erythropoietin (EPO) levels were recorded pre and posttransplant. Peripheral smear, lactate dehydrogenase, iron and ferritin levels, serum creatinine, days of hospital stay, rejections, infections, and immunosuppressive regime were recorded. Results: All patients were anemic within 1 week of transplantation and 40% had severe anemia. The prevalence of PTA at 3 months was 76.7%. PTA correlated with higher donor age, lower ferritin, Hb, and EPO levels in pretransplant period. However, even though EPO levels posttransplant were lower in patients with anemia, this correlation was not statistically significant. The lowest Hb correlated with Hb levels and dose of EPO-stimulating agents pretransplant. Conclusions: The prevalence of anemia is high in the immediate posttransplant period. High donor age, graft dysfunction, and iron stores before transplantation correlate with Hb levels at 3 months. It is prudent to maintain a better Hb in the pretransplant period to avoid PTA. Lower EPO levels before transplant may indicate immediate PTA. Correlation of EPO levels posttransplant with Hb needs further study.
Keywords: Anemia, chronic kidney disease, early anemia, erythropoietin, renal transplant
|How to cite this article:|
Talwar S, Nair R, Sreedharan S, Mathew A, Paul Z, Kurian G. Prevalence of posttransplant anemia in patients undergoing renal transplantation at a tertiary care center in Kerala - A prospective observational study. Indian J Transplant 2021;15:93-8
|How to cite this URL:|
Talwar S, Nair R, Sreedharan S, Mathew A, Paul Z, Kurian G. Prevalence of posttransplant anemia in patients undergoing renal transplantation at a tertiary care center in Kerala - A prospective observational study. Indian J Transplant [serial online] 2021 [cited 2021 Dec 5];15:93-8. Available from: https://www.ijtonline.in/text.asp?2021/15/2/93/319886
| Introduction|| |
Richard Bright first linked anemia to chronic kidney disease (CKD) over 170 years ago. Today, anemia in chronic renal failure is a well-known entity, the main cause being loss of endocrine function of the failing kidney, producing a fall in erythropoietin (EPO) production. Anemia is associated with a poor quality of life, increased cardiovascular disease, cognitive impairment, and mortality. Erythropoietin-stimulating agents (ESAs) form the mainstay of the treatment of anemia in CKD.
Renal transplantation is the renal replacement modality of choice for patients with chronic renal failure as it improves the overall quality of life. However, the overall posttransplantation estimated glomerular filtration rate (eGFR) is usually <60 ml/min/1.73 m2.
One may argue that since most of these patients will fall into the category of CKD on the basis of GFR, the data from studies on anemia in CKD may be extrapolated to this population.,, However, in the transplant setting, the presence of immunosuppression, rejections, infections, and surgical blood loss may complicate the picture. Hence, it is important to study anemia in transplant recipients as a separate entity.
As compared to anemia in CKD, the data on anemia in posttransplant patients are scarce. The prevalence of anemia reported ranges widely from 20% to 70%.
The current research mainly focuses on anemia either 3–6 months posttransplantation (early PTA) or after 6-month posttransplantation (late PTA). Data on anemia – prevalence and pathophysiology – within the first 3 months of transplantation (further referred to as immediate PTA) are low. In the immediate posttransplant period, factors other than surgical blood loss and hemodilution may play an important role. Other factors like induction and maintenance of immunosuppression, rejection, and infections may also contribute. We attempt to analyze the burden of anemia in our population in the immediate posttransplant period.
| Materials and Methods|| |
We performed a single-center prospective observational study, which included 30 consecutive patients who underwent renal transplantation from August 2016 to September 2017. Only patients who consented to participate, as per the signed informed consent, were included. Ethical clearance was obtained from the institutional ethical committee. Patients who underwent multiple organ transplantation were excluded from the study. Prior to transplant, iron status, ferritin, and transferrin saturation were recorded. Immediately pretransplant, the samples were collected for hemoglobin (Hb) and serum EPO levels. Patients were followed up for 3-month posttransplant. During the immediate posttransplant period, hematology and biochemistry were monitored daily. After discharge, routine outpatient follow-up was thrice weekly for the 1st month, twice weekly in the 2nd month, and once weekly in the 3rd month. Details of immunosuppressive agents, induction agents at the time of transplant, antimicrobial agents, duration of initial hospitalization, presence of infections, and episodes of rejection were recorded. All patients underwent a posttransplant Diethylene triamine pentaacetic acid (DTPA) renogram, and the GFR was recorded.
eGFR at 3 months was calculated for all patients using the Nankivell formula B. For each individual, the Hb nadir, i.e., the lowest value of Hb, during the period of follow-up was recorded. As in the TRESAM study, anemia was defined following the Clinical Practice Guidelines for Outpatient Surveillance of Renal Transplant Recipients, i.e., Hb levels of <13 g/dl for males and <12 g/dl for females and further subdivided as mild (males: 12–13 g/dl, females: 11–12 g/dl), moderate (males: 11–12 g/dl, females: 10–11 g/dl), severe (males: 8–11 g/dl, females: 8–10 g/dl), and very severe (Hb <8 g/dl or need for blood transfusion).
Statistical analysis was done using the IBM SPSS statistics 20 windows (SPSS Inc., Chicago, IL, USA).
Independent sample t-test was applied for comparing the mean of continuous parameters between the two groups. Fisher's extract test was used for finding an association between two categorical variables. Pearson's correlation coefficient was used for finding the degree of correlation between two continuous parameters. P < 0.05 was considered statistically significant.
The patient consent has been taken for participation in the study and for publication of clinical details and images. Patients understand that the names, initials would not be published, and all standard protocols will be followed to conceal their identity.
The study was approved by the Institutional Ethics Committee, Amrita Institute of Medical Sciences, Kochi: IECAIMS- 2017-NEPHRO-447. Study was carried out as per declaration of Helsinki.
| Results|| |
Thirty patients satisfied the inclusion criteria [Table 1].
The maintenance immunosuppression included steroids and calcineurin inhibitors in all patients (tacrolimus: 96.7% [n = 29] or cyclosporine [n = 1]). Mycophenolate mofetil (MMF) was used in 96.7% (n = 29/30). None of our patients received sirolimus.
Lymphocyte crossmatch was negative in 86.7% (n = 26) prior to transplantation. Induction was achieved by anti-thymocyte globulin (ATG) (56.7%, n = 17) and basiliximab (43.3%, n = 13). All patients received trimethoprim-sulfamethoxazole prophylaxis for Pneumocystis jirovecii and those induced with ATG received valganciclovir prophylaxis for CMV. During follow-up, 20% (n = 6) developed a biopsy-proven acute cellular or antibody-mediated rejection.
The prevalence of anemia was 100% at 1 week and 76.7% at 3 months post-transplantation. The Hb levels [Figure 1] showed a biphasic course – an initial sharp decrease followed by a gradual increase towards subnormal levels. This finding is in concurrence with the study done by Poesen et al., in Belgium.
|Figure 1: Hemoglobin levels in g/L (mean values) plotted for all patients (n = 30) on x-axis versus time line in relation to transplant. As seen the Hb levels fall from pre-tx period to 1 week posttransplant and then gradually increase over 3 months. Abbreviations: Tx: Transplant, Wk: Week, Hb: Haemoglobin|
Click here to view
Immediate PTA was seen to be significantly associated with pretransplant Hb, donor age, ferritin levels prior to transplant, measured GFR (by DTPA renogram) within 2 weeks of transplant surgery, and EPO levels before transplantation (P < 0.05). A borderline statistical significance was seen between the correlation of anemia and graft dysfunction (measured by serum creatinine) at 3 months. There was no statistical significance in the correlation between PTA and eGFR (measured by Nankivell formula) at 3 months
By Pearson's correlation test, pretransplant Hb and dose of ESA used before transplantation correlated significantly and directly with Hb nadir.
| Discussion|| |
The wide variation in the prevalence of PTA is likely due to the different definitions of anemia used and the variation in the posttransplant period across which the prevalence has been studied. Both the WHO and the American society of transplantation define anemia as Hb <12 g/dl in females and <13 g/dl in males.
All patients were found to have anemia after 7 days of transplantation, with 40% (n = 12) having very severe anemia. The prevalence of anemia then slowly decreased over time to 76.7% at 3 months with severe anemia in 26.6% (n = 8) [Table 2]. This finding is in concurrence with findings of Poesen et al., who reported the prevalence of posttransplant anemia in immediate posttransplant period at 98%, with 27.4% patients having very severe anemia and the overall prevalence declining to 76% at 3 months. In a study by Jones et al., the prevalence of anemia, using the WHO definition, was 88.6% at 1 month which is similar to our prevalence of 83.3%. Others have reported anemia in 19.3% to 35.5% of the patients at 6 months and among 12% to 25% of the recipients at 12-month posttransplant.
The Hb trends over a span of 3-month posttransplantation, in patients with anemia and in those without are shown in [Figure 2].
|Figure 2: Hemoglobin levels (mean values) in g/L, plotted over the x-axis versus time line in relation to transplant on y-axis. Two line graphs depict two groups of patients, those with anemia (blue) at 3 months and those without anemia (red) at 3 months. As seen in the figure, hemoglobin levels in both groups fall at 1 week post-tx and then gradually improve over 3 months to reach normal levels in the nonanemic group and subnormal levels in the anemic group. Abbreviations: Hb: Hemoglobin, wk: Week, Tx: Transplant, @: at|
Click here to view
As shown in [Table 3], Hb levels were significantly higher to start with pretransplant Hb in patients who did not develop anemia at 3 months (11.87 ± 1.79 g/dl) as compared to those who were anemic at 3 months (9.46 ± 1.13 g/dl); (P < 0.001). This association between immediate PTA and pretransplant Hb may help us postulate that a better control of anemia in the pretransplant period may help to prevent PTA at 3 months.
|Table 3: Results: Comparison between patients with and without anemia at 3 months posttransplantation|
Click here to view
The correlation between graft dysfunction (serum creatinine at 3 months) and measured GFR by DTPA at 2 weeks with immediate PTA suggests that graft function is a predictor of anemia at 3-month posttransplantation. Turkowski-Duhem et al. showed that posttransplant anemia at 6 months and 12 months was associated with higher serum creatinine at 3 months. Poesen et al. showed that graft function was an independent predictor of anemia at 3 months. This relationship between graft function and anemia can be explained by the fact that by normalization of renal function after transplant, once the graft kidney takes over, both the excretory and endocrine functions of the kidney should normalize. However, allograft dysfunction may lead to diminished endocrine capacity of the kidney and lead to anemia. Donor age was higher in the group with PTA at 3 months (48.65 ± 8.58 years) as compared to those who were nonanemic (34.12 ± 6.57 years); (P < 0.001). Similar conclusions were reached by Poesen et al., Vanrenterghem et al., and Jones et al. Vanrenterghem et al. reported female transplant recipients with lower mean Hb levels than the males. Shah et al. reported a higher level of Hb levels among males than females. However, in our study, there was no statistically significant difference in the prevalence of anemia across recipient gender or age. Our patients with PTA were older (recipient age-40.35 ± 13.124 years) as compared to those without anemia (30.29 ± 9.196 years). However, this difference did not reach statistical significance (P = 0.070), which may be due to the relatively small sample size of our study. We found varied results with few studies showing no significant correlation, while others show a correlation with higher recipient age.,,,
PTA at 3 months was associated with lower pretransplant ferritin levels (346.52 ± 213.994 ng/ml) as compared to those without anemia (1068.29 ± 607.773 ng/ml). However, there was no statistically significant difference in the pretransplant transferrin saturation levels. The finding that only 13.33% (n = 4) of the patients had a transferrin saturation <15% prior to surgery indicates that, to develop PTA, the presence of overt iron deficiency was not necessary. Lower iron stores (ferritin levels) were adequate to predispose these patients to PTA. These findings were in line with those of Poesen et al., who, in an observational study of 391 patients observed that pretransplant serum ferritin levels were significantly lower in anemic versus nonanemic recipients at 3 months.
Surgical blood loss, occult gastrointestinal bleeding, and the frequent phlebotomies may all contribute to iron deficiency in the immediate posttransplant period.
It should be noted here that in the patients who went on to develop PTA, 21.7% (n = 5) had significant perioperative blood loss and 8.6% (n = 2) had undergone re-exploration in the immediate postoperative period. It should also be noted that out of these five patients, four required blood transfusion (n = 4). These patients, in spite of adequate treatment of the blood loss, went on to remain anemic at the end of 3 months. Thus, perioperative blood loss may have contributed to iron deficiency in postoperative period, hence causing PTA. This is in concurrence with Moore et al. who found that perioperative blood loss can lead to PTA even after 6 months.
The antimetabolite medications, including azathioprine and MMF, are known to cause anemia via bone marrow suppression.,, The mammalian target of rapamycin (mTOR) inhibitors may cause anemia via myelosuppression. Augustine et al. have shown in two concurrent cohorts of patients receiving either sirolimus (n = 87) or MMF-based (n = 127) immunosuppression that sirolimus-based therapy was an independent factor of anemia and was associated with lower Hb levels at 12-month posttransplantation. In our study, all patients received immunosuppression with tacrolimus and almost all received MMF. None received mTOR inhibitors. Due to a homogeneous immunosuppressive regimen, we could not evaluate for the effect of immunosuppressive agents on PTA.
Although the PTA was higher in patients with rejections and those who received ATG, this was not statistically significant. Among other parameters that might affect PTA are delayed graft function (DGF) and number of renal transplants., However, DGF was seen in only 6% of the patients (n = 2) and most of the patients in our study underwent renal transplantation for the first time (n = 28, 93.4%). Hence, the correlation between anemia and number of transplants/DGF could not be studied.
Similarly, there was no statistically significant correlation between infections posttransplantation and PTA. About 36.6% (n = 11) had infections in the posttransplant period. Urinary tract infections were seen in eight patients (26.6% of the total cohort), while 1 each had hepatitis B and C (chronic) and 1 developed Cytomegalovirus (CMV).
Only 1 patient of the entire cohort had an evidence of hemolysis along with a biopsy-proven TMA. All other patients had normal lactate dehydrogenase levels and peripheral smears.
The mean Hb nadir in the cohort was 7.24 ± 0.88 g/dl. There was no statistically significant difference in the Hb nadir value between patients with anemia at 3 months (7.07 ± 0.843 g/dl) and those without anemia (7.8 ± 0.808 g/dl). It was observed that this Hb nadir was reached in 4.66 ± 2.48 days. Hb nadir was independently associated with lower pretransplant Hb and higher dose of ESA in the pretransplant period. There was no correlation between Hb nadir and pretransplant ferritin values. The above findings can be explained by postulating that in patients with already low pretransplant Hb, the Hb nadir value could be lower due to surgical blood loss. The fact that patients with higher pretransplant Hb also developed a significant drop and reached an almost similar Hb nadir level and then improved to be nonanemic at 3 months, suggesting that factors other than pretransplant Hb levels and surgical blood loss may contribute to PTA. This improvement in Hb may be attributed to higher pretransplant iron stores (ferritin levels) in these patients.
After renal transplantation, there is an immediate and large production of EPO. This is followed by a smaller and sustained increase in EPO levels at 4-week posttransplantation. We observed that EPO levels immediately pretransplant were significantly lower in the patients with anemia at 3 months (4.41 ± 4.30 U/l) as compared to those without anemia (17.44 ± 4.17 U/l).
The EPO levels after 4 weeks of transplantation were also lower in the group of patients with anemia at 3 months (22.99 ± 12.69 U/l) as compared to those without anemia (30.84 ± 23.29 U/l); however, this difference did not reach statistical significance. The above findings were similar to those of Turkowski-Duhem et al., in which the factors which independently correlated with anemia at 6-month posttransplantation included the serum EPO levels at the time of transplantation.
To the best of our efforts, we have not found any study correlating posttransplant EPO levels with anemia. The absence of statistical significance in our study in relation to low EPO levels posttransplant may be due to the reason that EPO production may be altered by factors like graft dysfunction, inflammation, or infections. In some patients, anemia may be due to EPO resistance that may correspond to a higher EPO level. However, it was seen in our study that EPO levels rose significantly in both the groups from the baseline pretransplant values.
It was also noted that 46.6% (n = 14) patients required blood transfusions in the posttransplant period, in spite of a high threshold to for the same (Hb ≤7 g/dl). This was higher than the reported (21.5%) in the study by Poesen et al.
As per the recent research, at least from an immunological perspective, there is no objection against a more liberal transfusion policy posttransplantation. Furthermore, in our study, none of the patients received ESAs in the posttransplant period. Few randomized, prospective studies have specifically addressed the efficacy, effectiveness, and safety of ESA in kidney transplant patients. There may be a narrow window of therapeutic target Hb levels in kidney transplant recipients that can be evaluated only with prospective studies. The role of ESA in posttransplant anemia is unclear with no clear guidelines.
The homogeneity of our study population with regard to race, immunosuppressive, and antimicrobial therapy (all been shown to be important determinants of PTA) can be regarded both as a strength and limitation of this study. In addition, acknowledging the lack of widely accepted guidelines for administering ESA and blood transfusions in renal transplant recipients, these therapeutic measures are taken on an individual-based approach creating inevitable treatment bias. Our sample size was sufficient to predict the prevalence of anemia. However, to make more clear associations with other factors like EPO levels posttransplantation, a prospective study with a higher sample size may be required.
| Conclusions|| |
The prevalence of immediate PTA in high and severe anemia is often noted within the 1st week of surgery, which is multifactorial. High donor age, graft dysfunction at 3 months, and iron stores prior to transplantation correlate with low Hb levels at 3 months.
We can also conclude that it is prudent to maintain a better Hb level in the pretransplant period to avoid posttransplant anemia.
A significant EPO level rise is universally seen in transplant recipients. Lower EPO levels in the pretransplant period may be an indicator of immediate posttransplant anemia. The correlation of EPO levels posttransplant with Hb levels needs further study.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Boss JM. Richard Bright's “Reports of Medical Cases” (1827) in the development of renal physiology [proceedings]. J Physiol 1978;277:54P.
Karthikeyan V, Karpinski J, Nair RC, Knoll G. The burden of chronic kidney disease in renal transplant recipients. Am J Transplant 2004;4:262-9.
McClellan WM, Flanders WD, Langston RD, Jurkovitz C, Presley R. Anemia and renal insufficiency are independent risk factors for death among patients with congestive heart failure admitted to community hospitals: A population-based study. J Am Soc Nephrol 2002;13:1928-36.
Sarnak MJ, Coronado BE, Greene T, Wang SR, Kusek JW, Beck GJ, et al
. Cardiovascular disease risk factors in chronic renal insufficiency. Clin Nephrol 2002;57:327-35.
Poesen R, Bammens B, Claes K, Kuypers D, Vanrenterghem Y, Monbaliu D, et al.
Prevalence and determinants of anemia in the immediate postkidney transplant period. Transpl Int 2011;24:1208-15.
Nankivell BJ, Gruenewald SM, Allen RD, Chapman JR. Predicting glomerular filtration rate after kidney transplantation. Transplantation 1995;59:1683-9.
Vanrenterghem Y, Ponticelli C, Morales JM, Abramowicz D, Baboolal K, Eklund B, et al
. Prevalence and management of anemia in renal transplant recipients: A European survey. Am J Transplant 2003;3:835-45.
Beutler E, Waalen J. The definition of anemia: What is the lower limit of normal of the blood hemoglobin concentration? Blood 2006;107:1747-50.
Jones H, Talwar M, Nogueira JM, Ugarte R, Cangro C, Rasheed H, et al
. Anemia after kidney transplantation; its prevalence, risk factors, and independent association with graft and patient survival: A time-varying analysis. Transplantation 2012;93:923-8.
Turkowski-Duhem A, Kamar N, Cointault O, Lavayssiere L, Ribes D, Esposito L, et al
. Predictive factors of anemia within the first year post renal transplant. Transplantation 2005;80:903-9.
Yabu JM, Winkelmayer WC. Posttransplantation anemia: Mechanisms and management. Clin J Am Soc Nephrol 2011;6:1794-801.
Mix TC, Kazmi W, Khan S, Ruthazer R, Rohrer R, Pereira BJ, et al
. Anemia: A continuing problem following kidney transplantation. Am J Transplant 2003;3:1426-33.
Moore LW, Smith SO, Winsett RP, Acchiardo SR, Gaber AO. Factors affecting erythropoietin production and correction of anemia in kidney transplant recipients. Clin Transplant 1994;8:358-64.
Gossmann J, Kachel HG, Schoeppe W, Scheuermann EH. Anemia in renal transplant recipients caused by concomitant therapy with azathioprine and angiotensin-converting enzyme inhibitors. Transplantation 1993;56:585-9.
Shipkova M, Spielbauer B, Voland A, Gröne HJ, Armstrong VW, Oellerich M, et al
. cDNA microarray analysis reveals new candidate genes possibly linked to side effects under mycophenolate mofetil therapy. Transplantation 2004;78:1145-52.
Kuypers DR, Claes K, Evenepoel P, Maes B, Vanrenterghem Y. Clinical efficacy and toxicity profile of tacrolimus and mycophenolic acid in relation to combined long-term pharmacokinetics in de novo
renal allograft recipients. Clin Pharmacol Ther 2004;75:434-47.
Kim MJ, Mayr M, Pechula M, Steiger J, Dickenmann M. Marked erythrocyte microcytosis under primary immunosuppression with sirolimus. Transpl Int 2006;19:12-8.
Augustine JJ, Knauss TC, Schulak JA, Bodziak KA, Siegel C, Hricik DE. Comparative effects of sirolimus and mycophenolate mofetil on erythropoiesis in kidney transplant patients. Am J Transplant 2004;4:2001-6.
Besarab A, Caro J, Jarrell BE, Francos G, Erslev AJ. Dynamics of erythropoiesis following renal transplantation. Kidney Int 1987;32:526-36.
Sun CH, Ward HJ, Paul WL, Koyle MA, Yanagawa N, Lee DB. Serum erythropoietin levels after renal transplantation. N Engl J Med 1989;321:151-7.
Pfeffer MA, Burdmann EA, Chen CY, Cooper ME, de Zeeuw D, Eckardt KU, et al
.; TREAT Investigators. A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med. 2009 Nov 19;361(21):2019-32. doi: 10.1056/NEJMoa0907845. Epub 2009 Oct 30. PMID: 19880844.
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]