Management of postkidney transplant anemia – is it feasible to maintain patient and allograft survival?

Fedaey Abbas; Mohsen El Kossi; Ihab S Shaheen; Ajay Sharma; Ahmed Halawa

doi:10.4103/jesnt.jesnt_5_22

REVIEW ARTICLE

Year : 2022 | Volume : 22 | Issue : 3 | Page : 129-147

Management of postkidney transplant anemia – is it feasible to maintain patient and allograft survival?

Fedaey Abbas¹, Mohsen El Kossi², Ihab S Shaheen³, Ajay Sharma⁴, Ahmed Halawa⁵
¹ Department of Nephrology, Jaber El Ahmed Military Hospital, Safat, Kuwait; School of Medicine, Faculty of Health and Science, Institute of Learning and Teaching, University of Liverpool, Liverpool, UK
² School of Medicine, Faculty of Health and Science, Institute of Learning and Teaching, University of Liverpool, Liverpool, UK; Doncaster Royal Infirmary, Doncaster, UK
³ School of Medicine, Faculty of Health and Science, Institute of Learning and Teaching, University of Liverpool, Liverpool, UK; Royal Hospital for Children, Glasgow, UK
⁴ School of Medicine, Faculty of Health and Science, Institute of Learning and Teaching, University of Liverpool, Liverpool, UK; Royal Liverpool University Hospitals, Liverpool, UK
⁵ School of Medicine, Faculty of Health and Science, Institute of Learning and Teaching, University of Liverpool, Liverpool, UK; Sheffield Teaching Hospitals, Sheffield, UK

Date of Submission	31-Jan-2022
Date of Acceptance	02-Apr-2022
Date of Web Publication	22-Jul-2022

Correspondence Address:
Dr. Ahmed Halawa
Sheffield Teaching Hospital, Herries Road, Sheffield S5 7AU
UK

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/jesnt.jesnt_5_22

Abstract

Background Kidney transplantation has been established as the best therapy for end-stage renal disease. After transplantation and to provide a prolonged and safe patient and allograft survival, early and prompt diagnosis of posttransplant sequelae, for example, posttransplant anemia (PTA) in particular, is currently crucial. Timing of presentation of this disease has its effect on PTA development. The ‘early’ presented PTA (before 6 months) may differ clinically from the ‘late’ one (after 6 months) with respect to the underlying background. Although early PTA is multifactorial, allograft dysfunction is usually the underlying mechanism in the ‘late’ one. Furthermore, PTA is currently considered as an independent risk factor for the evolution of cardiovascular system events; the latter has been proved to be the first leading cause of death in this cohort of patients. The aims and objectives of this review is to evaluate critically the risk factors responsible for PTA development, its epidemiology, diagnostic criteria, etiology for both ‘early’ and ‘late’ PTA, the available therapeutic approaches for PTA, as well as the effect of PTA in allograft and patient survival. Methods Current available literature and analysis of various trials concerned with PTA. Results The impact of anemia on patients as well as allograft outcomes cannot be simply overlooked. Management of the early as well as late PTA is crucial. However, a variety of hazards of its therapeutic options should be thoroughly considered. Conclusions A lowered threshold of post-transplant anemia (PTA) awareness and its early management has its crucial impact on allograft as well as patient survival. Benefits of PTA correction is not only reflected on patients’ and allograft longevity but also on upgrading KTRs’ quality of life.

Keywords: Etiology of PTA, kidney transplant, therapy of PTA

How to cite this article:
Abbas F, El Kossi M, Shaheen IS, Sharma A, Halawa A. Management of postkidney transplant anemia – is it feasible to maintain patient and allograft survival?. J Egypt Soc Nephrol Transplant 2022;22:129-47

How to cite this URL:
Abbas F, El Kossi M, Shaheen IS, Sharma A, Halawa A. Management of postkidney transplant anemia – is it feasible to maintain patient and allograft survival?. J Egypt Soc Nephrol Transplant [serial online] 2022 [cited 2023 Mar 25];22:129-47. Available from: http://www.jesnt.eg.net/text.asp?2022/22/3/129/351713

Introduction

Considering that kidney transplant recipients (KTRs) have been categorized as chronic kidney disease (CKD) 3–5, CKD-related anemia has recently been established as a robust independent predictor of cardiovascular system (CVS) sequelae, the major leading cause of mortality rates (MR) in this cohort of patients [1–3]. Various studies have reported the multifactorial nature of this disease, with some patients with CKD showing a degree of anemia that reflects an advanced level of allograft dysfunction [4–7]. In this cohort of patients, we have to expand the field of workup to include nutritional deficits (e.g. hypoalbuminemia, vitamin B12, folic acid, and iron deficiency), effect of medications [renin-angiotensin-aldosterone system (RAAS) blockers, cytostatic medications, immunosuppressive agents, etc.], and monitoring infectious and inflammatory episodes (i.e. cytokine burden) [2, 8, 9].

Pro-inflammatory cytokines [interleukin (IL)-1β, tumor necrosis factor (TNF)-α, and interferon (INF)-γ] are well-known agents that may enhance anemia evolution, particularly among patients with diabetes and CKD with associated systemic illnesses, for example, systemic lupus erythematosus and systemic vasculitis [5,7]. Furthermore, the effect of hypoxia-inducible factor (HIF) on anemia evolution has been more evident. HIF is responsible for transcription of O₂-sensitive gene [erythropoietin (EPO) gene] as well as activities of other mediators, particularly the vascular endothelial growth factor, glucose transporters, and nitrogen oxide synthetases [10]. The relation between HIF and the major iron homeostasis regulator, hepcidin, has been thoroughly investigated [11]. Patients with CKD usually express increased active oxygen radical levels, which may induce the following hazardous sequelae:

(1) Accelerated HIF degradation rates.

(2) Inhibition of the EPO gene expression.

(3) Depression of the tubular cells’ adaptive quality to hypoxic events [12].

The role of sKlotho in ameliorating renal anemia has been recently stated. It has a prophylactic effect on the development of CVS events [13]. An increased level of hemoglobin (HB) up to more than or equal to 110 g/l is accompanied with a higher level of sKlotho, a cardiac/renal protective agent in anemia that can be managed by EPO/iron therapy in the CKD cohort [7, 9, 14].

Before dialysis, the type of CKD anemia is usually a normocytic normochromic one, but with frequent blood loss during dialysis, it can be changed to a hypochromic microcytic iron-deficiency anemia state. EPO therapy can also participate in depleting iron stores through increasing iron consumption [9,15]. The recent inclusion of the extended criteria donors and involving high-risk patients in kidney transplant (e.g. old aged KTRs, diabetic nephropathy, and rapidly progressive glomerulonephritis) has led to an increase in posttransplant anemia (PTA) prevalence [16]. With persistence of PTA, eccentric left ventricular hypertrophy (LVH) may ensue and congestive heart failure (CHF) may consequently develop [1, 17, 18]. Moreover, decreased HB is associated with decline in O₂ supplies to myocardial and other tissues leading to sympathetic nervous system activation, tachycardia, RAAS and antidiuretic hormone activation, Na⁺ and water retention, increased venous return, and eccentric LVH and CHF. Furthermore, sKlotho decline can result in fibroblast growth factor (FGF-23) increments, which is recently recognized as a uremic toxin; it level increases earlier as compared with parathyroid hormone with kidney function deterioration [19,20]. The elevated levels of FGF-23 and the diminished oxygen supplies to the cardiomyocyte may trigger apoptosis with the evolution of cardiac fibrotic alterations and consequently CHF [14, 19, 20].

Timely diagnosis of PTA as well as the eradication or limitation of its predisposing factors with early intervention to optimize HB levels is considered a pivotal strategy to limit CVS complications, decrease all-cause mortalities, decrease the burden of prolonged hospitalization, and improve the quality of life of KTRs [1, 9, 21, 22]. The KDIGO ‘Clinical Practice Guideline for Anemia’ aims to assess the underlying mechanisms of PTA and target better therapeutic approaches. Therapeutic options may include repletion of mineral and vitamin deficiencies, erythrocyte-stimulating agents (ESAs), and lastly, blood transfusion in severe cases. However, a crucial need for randomized controlled trials (RCT) to optimize the best care approach for KTRs is currently warranted. The aim of this article was to evaluate the available data concerned with the early diagnosis and the possible therapeutic approaches and to guide the transplant clinicians for better PTA management [14].

Discussion

Definition

According to the WHO criteria, anemia can be defined as HB value of less than 12 g/dl in females and less than 13 g/dl in males. An anemic episode can be defined as two successive episodes of declined HB followed by two successive normal HB occasions [23]. Measurement of HB level can be measured through the normal complete blood cell testing. Severity of anemia is currently considered as HB level less than 11 g/dl in various studies [24–27].

Types of posttransplant anemia

PTA could be either transiently episodic or continuously permanent. It can also be seen early (<6 month) (early PTA) or presents late (>6 months) (‘late’ PTA) [28].

(1) ‘Transient’ PTA: almost 60% of KTRs may show recurrent episodes of PTA that can be observed in the following conditions:
- (a) Decline in allograft function [glomerular filtration rate (GFR) <60 ml/min, serum creatinine >190 mmol/l].
- (b) Recurred acute rejection.
- (c) Re-transplant (more common in females).
- (d) Elderly donors more than 60 years.
- (e) Deficient iron stores (ferritin <100 mg/l).
- (f) Diabetic KTRs.
- (g) Secondary hyperparathyroidism.
- (h) Opportunistic infection with elevated C-reactive protein (CRP) level more than 50 mg/ml.
- (i) Rapamycin and mycophenolate mofetil (MMF) combined therapy.
- (j) RAAS blockers or azathioprine and allopurinol combination therapy [1, 9, 28].
(2) ‘Permanent’ states of PTA may be observed in 30–40% of adult KTRs and in 60–80% of pediatric KTRs [29,30].
(3) ‘Early’ PTA can be seen at the first 6 months after transplant and is currently reported to be two to three times more common as compared with ‘late’ PTA, which can be observed 6 months after transplant [30,31]. Prevalence of the ‘early’ presented PTA is usually observed to be higher despite the preoperative vigorous control of PTA via ESAs (on regular hemodialysis, ‘HDX’) and rapid rise of EPO supplies after successful transplant. Early PTA may be explained by three main reasons:
- (a) Associated inflammatory states.
- (b) Perioperative blood losses.
- (c) Hyperparathyroidism-associated osteodystrophy.
(4) ‘Late’ PTA can present 3 months postoperatively. The early PTA becomes less intense as the process of erythropoiesis recovers; nevertheless, after 4–5 years, the possibility of PTA evolution is increased (‘late’ PTA) with progressive decline of allograft function related to the following:
- (a) Cyclosporine (CyA) nephropathy.
- (b) Chronic allograft rejection.
- (c) Posttransplant de novo glomerulonephritis.
- (d) Recurrent diseases after transplantation.
- (e) Late comorbid diseases, for example, malignancy and infectious states [32].

The inverse correlation between serum creatinine concentration and HB levels is mostly observed in KTRs with the lately developed PTA, as also typically seen in patients with CKD in general [1, 14, 21, 31].

Epidemiology

Despite the expected reversal of CKD anemia after kidney transplantation, almost 20–51% of KTRs may experience PTA along their posttransplant period [23,33–35]. Regardless of the magnitude of anemia severity, many authors might prefer to classify PTA according to the timing of presentation into ‘early’ PTA (<6 months after transplant) and ‘late’ PTA (>6 months) [25, 35, 36]. Although the reported prevalence of ‘early’ PTA approached 50% in various series [25, 33, 37], the prevalence of the ‘late’ PTA varied from 23 to 35% according to the timing of study performance along 8 years after transplantation [24, 33, 37–39].

General considerations

Anemia in chronic kidney disease

Renal anemia is a relentless sequela of CKD progress [1,2] and often develops if the GFR declines to less than 60 ml/min/1.73 m² (CKD 3–5). It is worthy to mention that if the GFR declines to less than 43 ml/min/1.73 m², a direct relation between estimated GFR and HB levels has been observed (for every 5 ml/min/1.73 m² decline of the GFR, a drop of HB level of 3 g/l will ensue) [1, 2, 21]. In addition, the degree of HB decline can be considered an indication of CKD progression. PTA has been recently recognized as an independent predictor of CVS events. The latter is established as the major cause of mortalities among patients with CKD. Evolution of PTA may be attributed to the following:

(1) Shortened red blood cell (RBC) survival.

(2) Decline of endogenous EPO production.

(3) Altered erythroid progenitor receptors’ sensitivity to EPO action.

(4) Diminished iron stores, which may be attributed to the following:
- (a) iron deficiency or
- (b) decreased iron availability, owing to high load of ‘hepcidin’ (that result from inflammatory changes associated with chronic uremia) [1, 2, 8].

Additional pathogenetic mechanisms of CKD-related anemia may include folate and vitamin B12 deficiencies that result from nutritional deficits and chronic inflammatory status, leading in the end to apoptotic immature erythroblasts [14, 40, 41].

Effect of comorbidities

In certain types of CKD, patients may express more intense anemia that is not correlated to their degree of renal dysfunction severity, a finding that may involve many factors that augment the severity of anemia, for example, inflammation and infectious episodes (cytokines burden), effect of medications (RAAS blockers and immunosuppressive agents), and nutritional deficits (low albumin, vitamin B12, folic acid, and deficient iron stores) [14,15].

Diabetes mellitus

Diabetic patients – in particular – have an extra load of factors that may aggravate their anemia, that is, chronic inflammatory and pro-inflammatory cytokines (e.g., IL-1β, TNF-α, and INF-γ). Their incremental level could be observed even before kidney failure becomes clinically evident. Of note, 10% of diabetic patients with normal kidney function may develop anemic episodes [42]. In one series performed on diabetics with normal kidney function, diabetes mellitus was reported to be an independent determining factor for HB level alterations. Additional contributing factors may be engaged in PTA development in diabetics, for example:

(1) RAAS blocker therapy [5,43].

(2) Chronic inflammatory status that may result in functional iron deficiency.

(3) Nonselective urine protein excretion with transferrin and EPO losses.

(4) Deficient EPO supplies owing to renal efferent sympathetic denervation in patients with diabetic neuropathy/nephropathy.

A unique epidemiological study conducted on a wide range of patients with CKD stage 3A reported that diabetics have expressed anemia two times more frequently than nondiabetic patients (60.4 vs. 26.4%). Diabetic patients also showed higher levels of serum ferritin, an acute-phase reactant that may show an underlying ongoing subclinical inflammatory process [6]. Patients with associated comorbidity (systemic lupus erythematosus and systemic vasculitis) may also express anemic episodes at earlier CKD stages (e.g. CKD 1/2).

Glomerulonephritis

Another contributing factor to anemia evolution is the exacerbating glomerulonephritis of an associated systemic disease. This glomerulonephritis activity may induce cytokine-induced alterations of the erythropoietic process and the evolution of chronic disease-related anemia. Analytic criteria of iron metabolism may characterize this type of anemia of chronic disease. Metabolic disorders of iron are primarily accompanied by increased iron absorption with retained iron in the reticuloendothelial system [4, 14, 41, 44].

Role of hypoxia-inducible factor

The role of HIF in the development of kidney disease-related anemia has been recently recognized [10,12]. HIF is responsible for the transcription of oxygen-sensitive genes (EPO gene) as well as activities of other vital mediators, particularly vascular endothelial growth factor, glucose transporters, and nitric oxide synthetases. Kidney is the normal site for persistent expression of HIF. It is a heterodimer that is composed of α and β subunits. HIF β-subunit expression plays a vital role in response to xenobiotics when a heterodimeric transcription compound utilizing ‘aryl hydrocarbon’ receptor has been constructed. On the contrary, partial O₂ pressure has the ability to regulate α subunit of the HIF-compound (HIF-1α and HIF-2α). With lack of hypoxic states, degradation of HIF-1α and HIF-2α progresses faster.

With enough O₂ supplies to the body tissues, enzyme FIH (factor responsible of HIF inhibition) affects ‘asparagine’ hydroxylation, consequently precluding the rise in transcriptional HIF-1α activity. With HB decline, α-subunit degradation is prohibited leading to HIF-1 β-cytochrome P300 complex formation [10,40]. Consequently, the binding of the active HIF complex to the complementary location of the EPO locus will trigger its synthesis. In addition to hypoxic burden, transcriptional HIF-1 activity can be currently triggered by nitric oxide, TNF-α, IL-1, as well as angiotensin II. So, HIF-1 also participates in regulating angiogenesis, glucose, and iron homeostasis[10]. HIF is primarily considered a pivotal participant in EPO production. In addition to renal production of EPO, hepatic production also can occur but to a lesser extent. In case of renal insufficiency, extra-renal EPO production cannot recompensate its renal deficit [45].

Effect of hypoxia-inducible factor-2α on hepcidin

The effect of HIF-2α on hepcidin (the major iron hemostatic regulator) has been declared; both hypoxia and iron deficiency can inhibit hepcidin synthesis, leading to stimulation of intestinal iron absorption [11]. HIF may interact with iron via iron-regulated proteins (IRPs) IRP-1 and IRP-2. With decline of the stored iron, IRP–IRE complex prohibits degradation of transferrin receptor and consequently stimulates intracellular iron uptake. However, if the stored iron is satisfactory, IRP–IRE complex is deactivated, proceeding to protosomal catabolism; consequently, iron absorption cannot be performed.

Moreover, HIF-2α after translation precludes the occurrence of intensified iron deficits [10, 37, 40]. The elevated active O₂ free radicals in CKD may enhance HIF-1α catabolism and prohibit an expressed EPO gene; consequently, the adaptation mechanism of renal tubular cells to hypoxic events is impeded [12]. Hyperglycemia in patients with diabetic nephropathy particularly with associated autonomous neuropathy may result in HIF-1α catabolism and inadequate EPO synthesis [5, 9, 42]. HIF-1α blood levels are usually declined among anemic CKD cohorts (normal: 1.5–6.0 pg/ml in adults and in pediatrics >14 years.). Murine anti-serum and monoclonal anti-HIF-1α molecular antibodies are currently utilized for HIF estimation [1, 12, 14].

Role of sKlotho, Klotho, and chronic kidney disease anemia

It has been observed that the circulating type of Klotho (sKlotho) humoral protein has a protecting pleiotropic effect on the CVS system [13,46]. Therefore, a sufficient sKlotho expression can be considered as a protective umbrella for the renal as well as the CVS systems. Recently, a direct linear relationship has been proved between GFR decline and the drop of sKlotho level [47]. ‘Klotho,’ which has been early identified by M. Kuro-o, is normally produced by renal tubular tissues. ‘Klotho’ has been recognized as a very sensitive indicator for anemia, oxidative stress, inflammatory stats, as well as intrarenal rise of angiotensin II.

Klotho and fibroblast growth factor-23

FGF-23, which is normally manufactured by osteocytes, usually regulates phosphorus, vitamin D, and parathyroid hormone metabolic activities. Nevertheless, elevated levels of FGF-23 are usually accompanied by an increased risk of cardiac death. A given explanation to FGF-23 cardiac effects may be attributed to the nonselective linkage to the myocardial FGF-4 receptors, considering the elevated serum FGF-23 in association with a continuous decline of Klotho levels (an FGF-23 co-receptor) with CKD progress, particularly seen in untreated anemia [39]. Milovanov et al. [14] have reported certain correlations that linked FGF-23 to cardiac troponin-I, which could be explained by the potential cardiotoxic effect of FGF-23 on the myocardium; therefore, cardiac troponin-I can be clinically detected. Considering that hypoxia is an independent risk agent for sKlotho decline in renal patients, serum Klotho correction is urgently requested to protect the hearts of patients with CKD. Consequently, patients with CKD who are amenable for anemia correction via EPO/iron therapy in order to salvage ‘sKlotho’ availability would have a potential protection via ameliorating the cardiovascular risk [13, 14, 27].

Diagnosis

Diagnostic evaluation

Diagnostic tools of KTRs should involve identifying ‘the ordinary’ causes of PTA exactly as that in nontransplant public, that is, RBC indices, reticulocyte count, serum iron levels, total iron-binding capacity, percent transferrin saturation (TSAT), serum ferritin, folate levels, vitamin B12, as well as other tests involving hemolysis detection (haptoglobin) if clinically warranted (increased reticulocyte count, lactate dehydrogenase, and indirect bilirubin levels). Moreover, particular risk factors of anemia that could be specifically attributed to kidney transplantation, for example, medication effects (immunosuppressives and antimicrobial) and infectious episodes, should also be thoroughly evaluated. According to the published data, anemia workup should be fulfilled almost 3 months after transplantation as timely diagnosis and prompt therapy would provide a beneficial prognostic effect [38].

Diagnostic criteria

The following are the references to the WHO criteria for anemia diagnosis [2,9]:

(1) HB less than 130 g/l, hematocrit less than 39%, RBCs count less than 4.0 mln/mcl, in males.

(2) HB less than 120 g/l, hematocrit less than 36%, RBCs count less than 3.8 mln/mcl, in females.

(3) HB less than 110 g/l, hematocrit less than 33%, in pregnant females [14].

CKD anemia (KTRs can be considered as CKD 3–5) is usually normocytic normochromic. For prompt diagnosis of anemia, the following parameters should be fulfilled: HB levels, main RBC indices (mean corpuscular volume, mean cell HB, reticulocytes number, ferritin levels, and TSAT), vitamin B12, and folate levels [1, 9, 21]. Reticulocyte count in anemic patients with CKD is often normal or mildly elevated depending on the intensity of bone marrow erythropoietic activity [14]. In spite of the presence of low EPO levels, an elevated immature reticulocyte fraction (representing an active bone marrow erythropoiesis) has been observed [1, 21, 40], which may be explained by the triggering effect of previous blood losses during HDX on enhancing medullary erythropoiesis. With prolonged period of continuous HDX, type of anemia may be changed into hypochromic microcytic iron deficiency anemia for two reasons:

(1) Repeated blood losses during dialysis.

(2) EPO therapy consuming impact on iron stores.

Once hypochromic microcytic type of anemia has been developed, HB in reticulocytes will be diminished [15,48]. Functional iron deficiency can be discovered via TSAT coefficient determination, and the hypochromic RBCs % can be also recognized using flow cytometry [1, 9, 21]. A combination of elevated serum ferritin level and low-TSAT value may shed light on enhanced ‘hepcidin’ activity, which usually denotes an underlying inflammatory process that can be confirmed by an elevated CRP level (>50 mg/dl) [8, 45, 49]. With elevated CRP levels, patient should be sought for an inflammatory background (e.g. underlying infection and systemic inflammatory diagnosis), and an antimicrobial and/or anti-inflammatory agent could be instituted before the start of ESA therapy [1, 9, 14, 21, 41, 49].

Etiology of the posttransplant anemia

PTA is usually multifactorial in origin ([Table 1] and [Fig. 1]); however, the major underlying mechanism of PTA development is the endogenous decline of EPO supplies, which is frequently accompanied by relative/absolute iron deficiency [30]. Optimization of EPO synthesis is usually expected after successful renal transplant with immediate allograft function but could be delayed if delayed graft function (DGF) developed for any reason. A frequently observed cause of PTA development is ‘EPO resistance,’ which can be seen with the following:

Table 1: Etiology of posttransplant anemia development [14]

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Figure 1: Common causes of posttransplant anemia [50]. Aza, azathioprine; CMV, cytomegalovirus; CyA, cyclosporin; EPV, Epstein-Barr virus; MMF, mycophenolate mofetil; PTLD, posttransplant lymphoproliferative disorders.

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(1) Frequent rejection episodes involving the allograft.

(2) Severe secondary form of hyperparathyroidism. And more often

(3) The presence of deficient iron stores [28–31].

Almost 40–50% of KTRs may express an absolute or relative iron deficiency that is usually accompanied by PTA development. Deficient iron stores may develop owing to several factors, for example:

(1) Gastrointestinal tract blood losses.

(2) Treatment with NSAID.

(3) Perioperative blood losses.

(4) Corticosteroids therapy [1,29].

(5) Direct and indirect anticoagulant therapy.

(6) Pretransplant deficient iron stores in KTRs.

(7) Chronic infectious states with elevated CRP level.

(8) Frequent small-scale blood losses during blood sampling [29].

(1) A pivotal cause of PTA development is the effect of iatrogenic agents, which may:
- (a) Suppress erythropoiesis.
- (b) Impede iron metabolism.
- (c) Augment the resistance to EPO action [29,30].
(2) In contrary to its latter action, corticosteroids may antagonize the myelotoxic effect of cytostatic agents, involving iatrogenic hypoplastic PTA, owing to the following:
- (a) Direct stimulatory effect on erythropoiesis and granulocytopoiesis.
- (b) Its direct effect on the pharmacodynamics of cytostatic agents [1,29].
(3) Several reports have also declared the role of RAAS blockers in PTA evolution. RAAS blockers have currently two major effects:
- (a) They impede EPO synthesis by blocking the RAAS.
- (b) Elevated tetrapeptide AcSDKP levels (an endogenous erythropoietic suppressor).

However, the suppressive effect of anti-RAAS agents on erythropoiesis is highly dose related. On the contrary, RAAS blocker combined with either azathioprine or allopurinol may augment their negative effect on erythropoiesis to a very serious level [1, 21, 29, 31].

Role of immunosuppressives

Of note, CyA in a higher dose given early posttransplant may trigger EPO synthesis in allograft with DGF due to vasoconstriction and RAAS activation, but with no corresponding rise in HB level. The prolonged use of calcineurin inhibitors may induce the development of calcineurin inhibitors toxicity (e.g. progressing tubulointerstitial fibrosis) with EPO synthesis decline and PTA progression. The myelosuppressive effect of SRL may be intensified with the addition of MMF. PTA may be observed in 30–57% of patients with this combination where the magnitude of HB drop can be correlated with SRL dosage. The myelosuppressive effect of the newly introduced cytostatic agents in the recent immunosuppressive regimens may necessitate the augmentation of EPO therapeutic dosage to antagonize this suppressive effect [1, 9, 14, 29, 31].

Risk factors of posttransplant anemia

A variety of risk agents have been involved in PTA evolution:

(1) Diabetes mellitus.

(2) Re-transplant.

(3) Female sex.

(4) Elderly KTRs over 60 years.

(5) Uremic hyperparathyroidism.

(6) Deficient iron stores (ferritin <100 µg/l).

(7) Recurrent episodes of acute transplant rejection.

(8) Persistent infectious episodes with elevated CRP level more than 50 mg/ml.

(9) Decline of allograft function (GFR <60 ml/min, serum creatinine >190 mmol/l).

(10) Drug combinations, for example, rapamycin plus MMF, and RAAS blockers plus azathioprine or allopurinol) [1, 29, 31].

Furthermore, PTA has been reported to be a considerable risk factor for the acute allograft dysfunction as well as for the long-term mortality of KTRs [50]. The early presented PTA may deteriorate allograft function immediately after transplant [28]. Early PTA may also induce the following deleterious effects:

(1) Deterioration of hypoxia in the allograft’s medullary zone.

(2) Augmented ischemia-reperfusion injury with a higher risk of (i) ischemic ATN, (ii) acute abrupt reaction, and (iii) acute pyelonephritis.

(3) Slows down regenerative processes in the epithelial lining of the convoluted tubules in transplant recipients (TR) with DGF [51].

In addition, the reported extra-renal complications of the ‘early’ presented PTA may include the following:

(1) Arrhythmia.

(2) Deterioration of CHF.

(3) Exacerbation of cardiac ischemic events.

(4) Poor quality mobilization with poor exercise performance.

(5) Blood transfusion-related complications including viral infection transmission [14,28].

Rare causes of posttransplant anemia

Passenger lymphocyte syndrome

Passenger lymphocyte syndrome (PLS) could be – very rarely – a cause of the acutely presented hemolytic anemia. It is often seen after solid organ transplants and/or bone marrow transplant in a KTR with blood group A or B who received a kidney from a donor with blood group O or a Rh-positive KTR who received an organ from a Rh-negative donor. Patients with PLS are mostly seen with either ABO or Rh mismatching; however, the anti-Kidd and Lewis blood group antibodies have also been recognized as a predisposing factor for PLS development. Anti-recipient RBC antibodies originating from donor’s B lymphocytes as well as plasma cells can induce hemolysis that can be seen early (few weeks) after transplantation. However, this process is frequently self-limiting. ABO antibodies will be cleared out 3 months thereafter. Direct Coombs testing and antibodies identification in serum are usually the preferred diagnostic tools. However, kidney transplantation has the lowest risk and intensity of hemolysis as compared with liver, heart, and lung transplant; the latter two have the highest risk [52]. Corticosteroids therapy is the usual therapeutic tool, whereas PE therapy, intravenous immunoglobulins (IVIG), or rituximab are further therapeutic options for resistant cases [53].

Acquired pure red cell aplasia

Acquired pure red cell aplasia (PRCA) is a rare disease that is characterized by the following:

(1) Intense anemia.

(2) Diminished reticulocyte count.

(3) Lack of erythroid precursors (<5%) in bone marrow, with no affection of all other cell lines.

The commonest causes of acquired PRCA are listed in [Table 2]); they are mostly related to organ transplantation. Among the recognized causes, PRCA is mostly induced by PVB19 infection in KTRs; other associations include thymoma, myelodysplastic syndromes, lymphoma (e.g. posttransplant lymphoproliferative disorders), leukemia, systemic autoimmune diseases, and medications [53].

Table 2: Common causes of acquired pure red cell aplasia [53]

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Erythropoiesis-stimulating agent-induced pure red cell aplasia

In 1998, ESA-induced PRCA was recognized. It usually appears owing to the production of neutralizing antibodies that are directed toward the EPO hormone (anti-EPO antibodies). Cases have been currently described with all recombinant EPO (rEPO) formulations. In early 2000s, ESA-induced PRCA was mostly attributed to the administration of subcutaneous epoetin α (Eprex); however, ESA-induced PRCA can be reported with all recombinant EPO forms. This problem has been managed via replacing human albumin by polysorbate-80, and the introduction of the prefilled syringe with uncoated rubber stopper [54]. However, recent data from the international prospective registries and the prospective immunogenicity surveillance registries have reported that PRCA is rarely observed with the current ESA agents [32]. Anti-EPO antibodies have the ability to cross-react with the endogenous EPO as well as with all rEPO molecules including darbepoetin α (Dα), consequently preventing EPO from reacting with its receptor. Timing of PRCA presentation is usually between 6 and 18 months, and at least 8 weeks on EPO therapy should have elapsed before PRCA could clinically manifest [55]. According to the 2012 KDIGO guidelines, ESA-PRCA should be investigated in a patient with CKD on ESA therapy for more than 8 weeks who expresses at least three criteria:

(1) Drop of HB level more than 0.5–1 g/dl/week or transfusion requirement of at least 1–2 U/week.

(2) Normal platelet and white blood cells count.

(3) Absolute reticulocyte count of less than 10 000/μl [56].

Recent formulations of rEPO depend on glycosylation and sialic acid content; therefore, different formulations of EPO have been available. One of these formulations is Dα. It is the second-generation ESA composed of two extra CHO chains and eight extra sialic acid components; this modification may allow this molecule to be less vulnerable to antibody evolution and make Dα-induced PRCA a very rare event and even not reported in KTRs. However, one case report has showed that anti-Dα antibody testing was positive by ELISA in a Dα-treated KTR [57]. Not all KTRs with positive anti-EPO antibody testing develop PRCA. A graduated set of assays have been currently available to identify the anti-EPO antibodies, for example,

(1) First, screening assays.

(2) Second, confirmatory assay.

(3) Finally, bioassay to define the neutralizing criteria.

(1) ELISA testing: it is widely available with lower sensitivity and specificity and permits high productivity. It is a rapid test, easy to apply, and relatively nonexpensive; so, it is considered a screening tool for antibody identification. False-positive and false-negative results are also possible.

(2) Radioimmunoprecipitation assay: it is considered the most accurate test for identification of anti-EPO antibodies. However, several defects still impede its wide applications:
- (a) It is not standardized.
- (b) Radiolabeled antigen is needed.
- (c) It is time consuming and difficult to automate.
- (d) It cannot detect the antibodies with lowered affinity.

On the contrary, surface plasmon resonance (Biacore) analysis can detect the rapidly dissociated, low-affinity antibodies that cannot be identified by ELISA and radioimmunoprecipitation testing; however, an expensive and special equipment is usually required. Bioassays are functional assays that help in the assessment of the neutralizing ability of the anti-EPO antibodies, where patient’s serum or immunoglobulin inhibits RBC precursor maturation in bone marrow [58]. Management of PRCA includes the following:

(1) All forms of rEPO agents (including Dα) should be withdrawn.

(2) Immunosuppressive therapy is required to clear the antibodies. Steroid therapy, cyclophosphamide, and CyA can be tried; however, in resistant cases, IVIG, plasma exchange (PE), and rituximab may be required [59].

In the case published in this issue, steroid dose increments and IVIG have been successfully tried with complete recovery [57]. Re-challenging EPO therapy may be considered in special situation if anti-EPO antibody level is extremely low. Intravenous EPO can be given with close monitoring of the absolute reticulocytic count, anti-EPO antibody levels, and systemic manifestations [60]. On the contrary, KDIGO guidelines recommend the administration of peginesatide for ESA-PRCA therapy. The latter agent, however, is a synthetic, peptide-based pegylated ESA that functions by triggering the EPO receptor; this agent was later held for vague serious untoward effects [53,61].

Salient features and symptomatology

Clinically, anemic patients can present with dizziness, shortness of breath, poor appetite, depression, impaired performance, exercise intolerance, and cognitive and sexual dysfunction. All can result in poor quality of life, frequent hospitalization, deterioration of kidney function, CVS events, and increased mortalities. A robust observation has been confirmed in various studies that HB decline can be considered as an independent risk factor for eccentric LVH and CHF. HB level drop will result in inadequate oxygen supply to organ tissues, which results in activated sympathetic nervous system (NS), tachycardia, activated RAAS/antidiuretic hormone, salt and water retention, edematous tissues, augmented venous return, and consequently, eccentric LVH/CHF. In untreated anemic patients with CKD, cardiac remodeling can develop as a consequence of the recently recognized new CVS/CKD markers, for example, sKlotho and FGF-23. The elevated levels of FGF-23 and the inadequate O₂ supply to the cardiomyocytes may result in cellular apoptosis, myocardial muscle fibrosis, and lastly, CHF ([Fig. 2]) [14,18–20].

Figure 2: Effect of anemia on LVH and CHF evolution in anemic patients with CKD in absence of timely management [14]. CHF, congestive heart failure; CKD, chronic kidney disease; LVH, left ventricular hypertrophy.

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Prognosis and patient and allograft outcomes

Outcome of posttransplant anemia, mortality rate, and graft failure

Almost all reports concerned with the prognostic effect of PTA showed significant relation with allograft loss [38]. Regarding patient outcome, PTA showed variable results with MRs. Positive correlation with MR has been shown in several reports, for example,

(1) In a French retrospective multicenter study involving 4217 KTRs showed that PTA after 12-month follow-up has a positive correlation with patient mortalities and allograft failure [62].

(2) An Austrian retrospective report involving 2031 KTRs, PTA had a significant correlation with MRs and allograft failure after 6 years of follow-up [63].

(3) Another retrospective series in Pennsylvania, USA, including 626 KTRs showed a higher risk of mortalities [64], and another retrospective study from Chicago, Illinois, USA, including 1023 KTRs, reported that PTA was correlated with the MR and allograft loss after 3 months of follow-up [27].

(4) Gafter-Gvili et al. [33] in their series that was conducted on 266 KTRs have also reported that PTA was accompanied by higher mortality levels, after a couple of years of follow-up.

(5) Recently, 1139 KTRs were studied with different PTA levels at any point of time between 6 and 18 months after transplant and have showed a composite endpoint of MR and graft loss [34]. Another Japanese report [65] and one study from Slovakia have showed similar results [38,66].

Cardiovascular system morbidity

Anemia was reported to be an independent risk factor for LVH development (with referral to the Cornell electrocardiographic voltage criteria) 1–5 years after transplant [67]. Both anemia and LVH have been correlated with the significantly increased risk of mortality. In addition, 638 adult KTRs with complete cardiac clearance have been studied retrospectively in two Canadian centers 1 year after transplant. Anemia has been recognized as an independent risk factor for de novo CHF [68].

Glomerular filtration rate decline

Gafter-Gvili and colleagues have reported in a retrospective study that estimated GFR drop has been observed with time in anemic KTRs. A difference of about 5.26 ml/min/1.73 m² in estimated GFR has been reported between 6 months and 2 years. An estimated GFR decline by 2.26 ml/min/1.73 m² was observed in anemic versus improvement in nonanemic KTRs [33,38]. In a prospectively randomized study, Correction of Anemia and Progression of Renal Insufficiency in Transplant Patients (CAPRIT) study [69], KTRs were randomly exposed to epoetin-β therapy to attain a target level of 13–15 or 10.5–11.5 g/dl. Optimization of PTA to a normal level of HB (13–15 g/dl) has the following effects:

(1) Amelioration of the rate of estimated GFR deterioration.

(2) Improved estimated Cr Cl and progression to end-stage renal disease (ESRD).

(3) Better death-censored allograft survival.

These findings declare two potential facts:

(a) Anemia is a culprit agent for estimated GFR deterioration.

(b) Correction of anemia may ameliorate the rate of estimated GFR decline, which is in agreement with other reports on patients with CKD.

A robust correlation between anemia and fast estimated GFR decline has been also reported in another Japanese cohort [38,70]. A comparison of three recent studies analyzing ESA effect on PTA has been shown in [Fig 3] [50].

Figure 3: Comparison of three recent studies analyzing ESAs in posttransplantation anemia. eGFR was not evaluated, and mortality increased at HB more than 14 g/dl in Heinze and colleagues. eGFR, estimated glomerular filtration rate; ESA, erythrocyte-stimulating agent; HB, hemoglobin.

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Differences in mortality between severe PTA, mild PTA, and no PTA over 10 years in CKD stages 3–5 have been also shown in [Fig. 4] [66].

Figure 4: Difference in mortality between severe PTA, mild PTA, and no PTA over 10 years in CKD stages 3–5. Kaplan–Meir plots showing higher mortalities during 10 years after transplantation in patients with CKD stages 3–5 with severe PTA compared with patients without PTA, P value less than 0.001 [66] (open access). CKD, chronic kidney disease; PTA, posttransplant anemia.

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Summary

All of these reports documented that anemia could be significantly correlated with allograft loss. Other studies, however, failed to document correlation to all-cause MR, but a significant correlation to allograft loss [71–73]. Gafter-Gvili and Gafter [38] have reported a correlation between anemia and mortalities, which was primarily related to the degree of anemia severity, that is, severe anemia (HB <11 g/dl) has been observed to be correlated to MR; however, this cannot be proved in mildly anemic KTRs. Both degrees (mild and severe types), however, were correlated to allograft loss. These results may provide an explanation to the discrepancy between various reports. Of note, the given association between anemia severity and mortality has been also confirmed in predialysis cohort of patients [74].

Degree of anemia severity

A very recent study by Schechter and colleagues conducted on 1139 KTRs has shown that the magnitude of anemia severity is evidently correlated to allograft loss as well as patient mortalities [23]. Several reports have also reported an association between PTA and the composite outcome of all-cause mortalities and allograft failure [25, 27, 62–64, 66, 72, 75], as well as isolated varieties: death-censored graft survival [34, 73, 74, 76, 77] and all-cause mortalities [25, 75, 78]. However, PTA was inconsistently linked to the increased rates of mortalities. In fact, several reports were not successful to link PTA with all-cause mortalities, despite proving an association with allograft failure [36, 63, 73, 76, 79–81].

Schechter et al. [23] have reported a robust association between PTA and the primary outcome of allograft loss and mortality, and with mortality as a sole variable. They have also reported PTA in 36% of KTRs included in their study, which was in agreement with other early reports that reported a PTA prevalence of 20–40% [23–27, 33, 39, 65–67, 72, 75, 80–87]. They have also reported a significant correlation between all-cause mortality and only with ‘severe’ anemia, which was in agreement with that observed by Heinze and colleagues, who found a passive correlation between MR and HB level in KTRs with ‘late’ PTA [23,88].

However, the results of Schechter and colleagues were not in agreement with other reports that showed no correlation between ‘late’ PTA and MR [71, 76, 79–81]. Most of these findings showed mild anemia with mean HB more than 11 g/dl. Death censored allograft failure was significantly correlated with the ‘late’ PTA by univariate and multivariate analyses in both anemic groups. However, this relation is weaker with mildly anemic patients.

On the contrary, Huang et al. [76] have observed that only the more intense levels of PTA (HB <11 g/l and < 10 g/l in males and females, respectively) were accompanied with lower 3- and 5-year graft survival rates, but this cannot be applied to all-cause mortality. Despite many reports have shown variable causes for PTA, most reports did not engage in clarification of the underlying etiology for PTA. Nevertheless, only two reports have shown that iron deficiency [86] and the percentage of hypochromic RBCs [89] can be considered predictors of the higher rates of all-cause mortality.

Effect of the underlying etiology

Schechter and colleagues were pioneer in reporting the correlation of ‘specific etiology’ of PTA and patient/allograft outcome, that is, PTA owing to acute kidney injury, rejection episodes, infectious episodes, or nutritional deficits can be correlated with a higher risk of patient’s death or allograft failure, whereas PTA with lack of a ‘specific cause’ is devoid of this correlation [23]. Frequency of the specific etiologies includes the following:

(1) Iron-deficiency anemia was prevalent in 35% of KTRs (13% of the cohort), in agreement with other studies [80,86].

(2) Folic acid deficiency was observed in 10% of anemic KTR, which is relatively low as compared with 23–41% in other reports [80, 90, 91].

(3) Vitamin B12 deficiency was prevalent in 24% of anemic KTRs, in agreement with the 17–24% range observed in other reports [90,91].

Role of red cell distribution width

Despite the reported significant association of posttransplant red cell distribution width (RDW) with a poor outcome in many clinical cohorts, the role of high RDW values in the prediction of allograft failure is still uncertain. Park and colleagues studied RDW in about 3000 Korean KTRs in a retrospective study at kidney transplant and 3 months after with a mean follow-up period of 6.6 years. They consider RDW in the upper quartile range an elevated RDW value (>14.9%). They found 679 KTRs with elevated RDW 3 months after transplantation. Patients with increased RDW have experienced allograft loss, a fact that cannot be corrected even after optimization of HB levels as well as other clinical variables. A 1% rise in posttransplant RDW showed also significantly correlate with patients’ outcome regardless of the anemia status. The worst outcome in this study has been observed with elevated RDW levels after transplant but never at baseline. Consequently, the posttransplant values of RDW may show significant association with KTRs outcome, regardless of the HB levels [78]. One of the most common laboratory panels in clinical practice is the complete blood cell count, with RDW routinely included. RDW is commonly applied in the differential diagnosis of anemia and in declaration of early iron deficiency. RDW has recently been admitted as a predictive criterion of clinical outcome, particularly among cardiac patients [92–103]. Moreover, increased RDW has been reported by a meta-analysis to be related to a poor prognosis [104,105]. The exact underlying mechanism of RDW effect on clinical outcome is not uncertain; however, the following mechanisms have been postulated:

(1) Inflammatory process.

(2) Deficient iron stores.

(3) Poor nutrition situation [95,106].

The role of kidney in hematopoiesis is well established; consequently, renal dysfunction can be associated with PTA as well as other hematological malfunctions, for example, altered hemostasis [107]. Kidney dysfunction is clinically related to altered RBC indices [95]. In patients with kidney dysfunction, RDW can be considered an eminent clinical prognostic factor [96,97]. A paucity of studies, however, exist for evaluation of the magnitude of the predictive value of RDW [99,100]. Despite several limitations, they reported that increased RDW level was associated with poor posttransplant outcome in KTRs. Nevertheless, it is still uncertain that posttransplant RDW is associated with allograft loss [88].

Park and colleagues reported the first study regarding the predictive value of posttransplant RDW as well as RDW elevations on the two most pivotal outcomes of KTRs, death-with-graft-function and death-censored-graft-failure, in a large transplant study with a long-term period of follow-up. RDW estimation has originally been applied in the differential diagnosis of anemia or iron deficiency; after anemia assessment was performed, RDW level was frequently neglected [78] ([Fig. 5]).

Figure 5: Association between posttransplant red cell distribution width and prognosis of KTRs, DWGF, and DCGF, according to presence of increased posttransplant RDW. Cumulative survival curve of study population. Y-axis indicated the cumulative survival and x-axis indicated the years from transplantation. Upper graph shows DWGF, and the lower graph shows DCGF. The black line indicates the cumulative survival of increased RDW (>14.9%) level at 3 months after transplant, and the gray line indicates the cumulative survival of others with nonelevated RDW (<14.9%). RDW, red cell distribution width, DWGF, death-with-graft function, DCGF, death-censored-graft failure [97]; KTR, kidney transplant recipient.

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Moreover, several reports denote that RDW can be correlated with general outcomes in the general population [98, 99, 108]. A few reports have been concerned with RDW in KTRs and its relation to poor outcome, perhaps due to lack of a standardized date of RDW value estimation as well as death-censored-graft-failure evaluation; the latter is one of the most prominent outcomes for KTRs [100,101]. Furthermore, RDW predictive significance was considered valid regardless of the following:

(1) HB values.

(2) Established anemia.

(3) History of ESA therapy.

(4) History of RBC transfusion.

Worst outcome, however, was observed in KTRs with normal basal RDW levels and RDW increments after transplantation, which suggests RDW alterations as a good prognostic factor [88]. The role of elevated RDW in inducing poor prognosis can be explained via several mechanisms:

First, RDW-related inflammatory criteria [95, 103, 104]:

(1) Park et al. [78] observed in their study that higher RDW in KTRs was associated with a higher values of serum ferritin levels, an acute-phase reactant that suggests an inflammatory role in inducing poor prognosis.

(2) Patients with high RDW values have a higher incidence of posttransplant infectious sequelae.

Second: defective iron metabolism that can be indicated from the association of decreased total iron-binding capacity and the higher serum ferritin levels. The observed significant correlation of diminished HB levels to the higher levels of RDW and the fact that anemia is a poor prognostic marker suggests that RDW increments can be considered an indicator for a poor hematopoietic profile even in early developed anemia [25,86].

Third: poor nutrition, that is, low serum albumin may be associated with high RDW levels [95].

Fourth: allograft dysfunction, as kidney is considered a vital hematopoietic organ, RDW increments may suggest an underlying deteriorated allograft function [95].

Regarding factors related to increased RDW, several factors have been included, for example, elderly, male sex, allograft dysfunction, and low HB levels and hypoalbuminemia [98, 100, 101, 109]; all were studied before and related to elevated RDW levels. Of note, history of smoking is related to higher RDW levels in general population [98,99]. In this study, deceased donor type was associated with elevated RDW values for the first time [100,101]. The effect of various agents on RBCs profile warrants further research.

To summarize

Posttransplant RDW was significantly correlated to KTR outcome. In view of the reported prognostic value of RDW among KTRs, this marker should be considered in the posttransplant follow-up of this cohort of patients for early assessment of KTR prognosis.

Therapy of posttransplant anemia

PTA management should be instituted by the reversal of any underling correctable cause (s), for example, iron, B12, and folic acid deficiencies. However, there are no particular recommendations dedicated for this cohort of patients [38].

Iron therapy in posttransplant anemia management

Despite the availability of several RCTs documenting the efficacious role of iron therapy in CKD-related anemia, iron administration for PTA therapy still warrants more workup. Schechter and colleagues have reported in a retrospective study that IV iron can improve HB levels and regress the rate of estimated GFR deterioration in KTRs; both parameters are more profound with low HB levels (i.e. <9.4 ± 1.2 g/dl) [23, 110, 111]. Another small RCT (104 KTRs) compared oral iron with a single dose of intravenous iron and showed no difference in the period needed to correct early PTA [112], but ‘late’ PTA was not included. Considering the reported better prognosis observed with PTA correction [69,78], it is reasonable to optimize HB levels to be in the higher side. However, the optimal approach to correct HB level is still uncertain.

Despite the abundant data observed in RCTs and meta-analysis of the role of iron therapy in patients with CKD [113], similar reports in KTRs are actually lacking. Deficient iron stores, with absence of anemia, has been considered an independent predictor for KTR mortality [86]. Gafter-Gvili and Gafter have conducted a small retrospective cohort trial including 81 KTRs who have received intravenous iron after transplant between year 2000 and 2009; this form of therapy administrated after transplant not only improves HB levels but also limits the rate of estimated GFR decline. Again, both items were intensified at a lowered level of HB [38,111].

Role of intravenous iron

Before commencing ESA therapy, iron status should be recognized with repletion of iron stores [110]. It is not certain in transplant community whether intravenous form of iron could be superior to the oral form or not. In a limited RCT conducted on 104 KTRs, the intravenous form of iron was compared with the oral one. No difference has been observed in time to PTA correction more than 11 g/dl [112]. However, in this trial, the lately presented PTA was not covered as it has been conducted early postoperatively. The benefit of intravenous iron, however, over the oral form has been established in patients with CKD either on dialysis or in the predialysis period [113]. Furthermore, a meta-analysis conducted on 103 RCTs assessing safety and efficacy of intravenous iron has showed absence of any robust risk concerned with severe drawbacks or serious infectious episodes [114]. Consequently, it is feasible to administer intravenous iron to KTRs for PTA management [38].

Indications of erythropoietin therapy

According to the KDIGO criteria, ESA should be started in patients with CKD only if the HB level is less than 10.0 g/dl, targeting a HB level of 11.5 g/dl [110]. However, the NKF-KDOQI guidelines admitted a special comment on these guidelines and have adopted the recommended FDA opinion of keeping the upper cut-off level of 11 g/dl [115].

Benefits of erythropoietin therapy

Considering the long-term sequelae of PTA on allograft longevity, patient’s survival, and quality of life, it is of utmost priority to commence the necessary maneuvers to normalize the HB decline and correct PTA to alleviate the burden of these sequelae. Primarily, it is essential to declare the possible underlying cause(s) of anemia, for example, blood losses and depleted iron stores, and manage them accordingly despite the presence of certain inevitable factors, for example, immunosuppressive agents. So far, the direct factor that is amenable for rapid correction is the absolute/relative EPO deficiency. A variety of ESAs are currently available with a remarkable set of benefits. In animal studies, ESAs can prohibit transplant glomerulopathy development via several mechanisms that are different from optimizing HB level, including the following:

(1) Immunomodulation.

(2) Upregulating anti-apoptotic agents.

(3) Preserving the intra-allograft expression of angiogenic agents [51,116–118].

Role of erythrocyte-stimulating agents in various trials

The target level of HB should be primarily determined, and the therapeutic approach, that is, ESAs and/or iron, must be identified. An Austrian report involving 1794 KTRs reported that PTA (HB <12.5 g/dl) was highly correlated to MR among recipients with and with no ESA therapy. Both groups have showed a decreased MR. Further rise of HB in ESA-treated group above the level of 14 g/dl was associated with a tendency to increased mortality, which was more pronounced at a HB level of more than 14 g/dl [78]. The elevated HB levels were significantly correlated with an improved allograft survival in the CARPIT TRIAL [69], where 125 KTRs were exposed to receive Epo-β to achieve a HB target of 13–15 g/dl (completely corrected) or 10.5–11.5 g/dl (partially corrected). It has been observed that the group with complete HB correction was associated with a decreased rate of estimated GFR deterioration and progression to ESRD as well as improvement of the death-censored allograft survival [35,36]. Comparing the partially corrected group to the completely corrected one showed a smaller decline in estimated GFR (i.e. 5.9 vs. 2.4 ml/min/1.73 m²), less progression ratio to ESRD (i.e. 21 vs. 4.8%), and elevated death-censored allograft survival (i.e. 80 vs. 95%). Furthermore, a better quality of life was also observed in the fully corrected cohort. Despite the small number of the studied KTRs, no cardiac events have been observed in the completely corrected group as compared with four (8%) patients in the partially corrected one [38].

The observations given by the CAPRIT trials obviously differ from that given in wider ones in the CKD community. The CHOIR trial [119] was conducted on 1432 patients with CKD 3–4 who have been randomized to get a target HB of 13.5 or 11.3 g/dl via Epo-α administration. The ‘Trial to Reduce Cardiovascular Events with Aranesp Therapy’ study involved type 2 diabetics and CKD 3–4. Candidates were randomized to either darbepoetin-α to attain a target HB of 13.0 g/dl or placebo administration. A rescue darbepoetin-α administered led to a drop of HB to a level of less than 9.0 g/dl [120]. Neither CHOIR nor TREAT trial has showed decrease in the risk of CVS events or a delay in CKD progression through normalizing HB via ESAs. The CREATE trial [121] was conducted in a similar design to the CAPRIT trial and conducted on 603 patients with CKD 3–5. Two levels of HB have been randomly assigned, 13.0–15.0 and 10.5–11.5 g/dl, via Epo-β administration. It has been shown in this trial that targeting higher level of HB may be associated with a significant demand for maintenance on dialysis therapy [38].

Again, there is no particular recommendation that could be dedicated for KTRs. The CAPRIT trial in KTRs is a small one that has the limitation of duration shortage (only 2 years); however, it is the only available RCT that managed this issue among the KTR cohort. This trial was in accordance with other large observational reports, such as Heinze et al. [88], who reported an optimal level of targeted HB in anemic KTRs should be at a higher level than that targeted in patients with CKD and should be titrated up to a level of 12–13 g/dl. The CAPRIT study design should be expanded and applied on a wider RCT scale and for a longer duration to recognize accurately the desired target HB level in this community.

Other opinions

However, the general attitude for ESA administration for PTA correction may be opposed by the findings observed in the Normal Hematocrit Study in dialysis (DX) patients and in the CHOIR, CREATE, and TREAT studies in non-DX-dependent CKD cases [119–121]. These reports either have observed a lack of benefit or a CVS harm with ESA therapy institution. So, in view of paucity of data concerning PTA in KTRs, current guidelines for CKD-associated anemia can be followed in the transplant community [122,123]. Interestingly, Heinze and colleagues in a retrospective analysis of Austrian KTRs in the Dialysis and Transplant Registry reported increased moralities with a target HB exceeding 12.5 g/dl via ESAs [78]. Of note, patients with increased HB values without ESAs showed better survivals. On the contrary, two more recent reports showed a beneficial use of ESAs in KTRs:

(1) An RCT by Choukroun et al. [69] reported a better survival as well as quality of life with administration of epoetin-β to increase HB level up to 13.0–15.0 g/dl, with no more added risk of serious CVS hazards ([Table 3]).

(2) Another more recent Japanese RCT reported diminished rate of decline of allograft function along 3 years of follow-up of KTRs with transplant glomerulopathy with targeting a HB level of 12.5–13.5 g/dl via EPO therapy with no reported serious adverse effects [124] ([Table 3]).

Table 3: Compared results, inclusion, exclusion criteria of three recent studies about posttransplant erythrocyte-stimulating agent therapy

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The contradictory results among these reports about ESAs in patients with CKD as well as in KTRs may be attributed to the variation in the background of CVS risk situations, ESA dosages, and the rate of HB optimization, in addition to other immunologic and nonimmunologic influences of PTA in KTRs, which may differ in patients with CKD from that in KTRs [51].

Blood transfusion

It is an essential practice to consider HB levels, overall clinical status, patient preference, and optional alternates during transplant-related decisions.

First recommendation

Restriction of the threshold for the transfused RBCs to be holding of blood transfusion until the level of 7 g/dl HB is currently recommended for hospitalized adults with hemodynamic stability, including patients with critical illness rather than the level of 10 g/dl HB (strongly recommended with moderate power of evidence). With preoperative preparation for orthopedic surgery, cardiac surgery, and KTRs with preexisting CVS events, the threshold for blood transfusion should be restricted to a level of 8 g/dl HB (strongly recommended, moderate quality of evidence). A restrictive blood transfusion threshold of 7 g/dl can be compared with the level of 8 g/dl; however, there is lack of RCT evidence for all categories. However, the aforementioned recommendations cannot be applied in two situations:

(1) KTRs with acute coronary syndromes or intense thrombocytopenia (patients with comorbid hematological or malignant illnesses with high risk of bleeding events).

(2) Chronically transfusion-dependent anemia (not recommended due to lack of sufficient evidence) [125].

Second recommendation

Patients should receive RBC units selected at any point of time within their licensed period (standard issue) rather than limitation to transfusion of only fresh (stored <10 days) RBC units (strong recommendation with moderate evidence) [125].

However, these recommendations may be limited by the increased risk of infection transmission, blood transfusion incompatibility, as well as the impeding impact on proceeding to another kidney transplant.

Conclusion

Lowering the threshold for PTA awareness and management has its crucial effect on allograft and patient longevity. Early diagnosis of PTA is very amenable, considering the clarity of its salient features and the availability of simple diagnostic techniques. This fundamental posttransplant care item is probably underestimated. A thorough survey of the underlying etiology, including rare causes, should be performed. Risk factors of PTA evolution, comorbidities, and a thorough revision of the current medications should also be promptly evaluated. Serial estimation of HB level concentrations and other related profiles is essential for a timely diagnosis and to avoid the development of serious complications like myocardial cell apoptosis and myocardial fibrosis.

Therapeutic approach of PTA may include iron therapy, ESAs, correction of hypovitaminosis, modulation of the immunosuppressive medications, as well as management of the underlying cause(s). Blood transfusion may be also cautiously considered in severe cases. However, more efforts should be exerted to clarify the effect of PTA severity on patient and allograft survival as well as the prognostic role of the underlying factors. Benefits of PTA correction are not only reflected on patient and allograft survival but also on enhancing the quality of life of KTRs.

Recommendations

A full detailed history in addition to a full battery of investigations should be accomplished in the serial PTA workup. Verification of the underlying cause(s) should be currently declared before the institution of any therapeutic approach. Of note, a lately presented PTA may denote an underlying allograft dysfunction.

Acknowledgements

Authors contributions: Dr Fedaey Abbas designed the study, did data collection, and wrote the manuscript. Mohsen El Kossi, Ihab S. Shaheen, and Ajay Sharma reviewed and edited the manuscript. Ahmed Halawa conceptualized and designed the study, supervised the data collection, and reviewed and edited the manuscript.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1.	KDIGO. Clinical practice guideline for anemia in chronic kidney disease. Kidney Int 2012; 2:1–335.
2.	Phrommintikul A, Haas SJ, Elsik M, Krum H Mortality and target haemoglobin concentrations in anemic patients with chronic kidney disease treated with erythropoietin: a meta-analysis. Lancet 2007; 369:381–388.
3.	Thorp ML, Johnson ES Effect of anemia on mortality, cardiovascular hospitalizations and end stage renal disease among patients with chronic renal disease. Nephrology 2009; 14:240–246.
4.	Ebben JP, Gilbertson DT, Foley RN, Collins AJ Hemoglobin level variability: association with comorbidity, intercurrent events, and hospitalizations. Clin J Am Soc Nephrol 2006; 1:1205–1210.
5.	Loutradis C, Skodra A, Georgianos P, Tolika P, Alexandrou D, Avdelidou A, Sarafidis PA Diabetes mellitus increases the prevalence of anemia in patients with chronic kidney disease: A nested case-control study. World J Nephrol 2016; 5:358–366.
6.	Kengne AP, Czernichow S, Hamer M, Batty GD, Stamatakis E Anaemia, haemoglobin level and causespecific mortality in people with and without diabetes. PLoS ONE 2012; 7:e41875.
7.	Milovanov YS, Kozlovskaya (Lysenko) LV, Milovanova LY, Markina MM, Kozlov VV, Taranova MV, Fomin VV Risk factors for anemia development in the early stages of chronic kidney disease. Ter Arkh 2017; 89:41–47.
8.	Keithi-Reddy SR, Addabbo F, Patel TV, Mittal BV, Goligorsky MS, Singh AK Association of anemia and erythropoiesis stimulating agents with inflammatory biomarkers in chronic kidney disease. Kidney Int 2008; 74:782–790.
9.	Kozlovskaya (Lysenko) LV, Milovanov Yu S, editors. Anemia. Brief guide. Moscow: GIOTAR Publish Group; 2016. 120.
10.	Volker HH Regulation of erythropoiesis by hypoxia-inducible factors Blood Rev 2013; 27:41–53.
11.	Garrido P, Ribeiro S, Fernandes J, Vala H, Bronze-da-Rocha E, Rocha-Pereira P, et al. Iron-hepcidin dysmetabolism, anemia and renal hypoxia, inflammation and fibrosis in the remnant kidney rat model. PLoS ONE 2015; 10:e0124048.
12.	Volker HH Hypoxia-inducible factor signaling in the development of kidney fibrosis. Fibrogenesis Tissue Repair 2012; 5(Suppl 1): S16.
13.	Xie J, Yoon J, An SW, Kuro-o M, Huang C-L Soluble klotho protects against uremic cardiomyopathy independently of fibroblast growth factor 23 and phosphate. J Am Soc Nephrol 2015; 26:1150–1160.
14.	Milovanov YS, Lysenko LV, Milovanova LY, Fomin V, Mukhin NA, Kozevnikova EI, et al. Anemia in chronic kidney disease and after kidney allotransplantation (systematic review) 2017. Doi:10.5772/ intechopen.69746. Available at: https://www.intechopen.com/chapters/56075
15.	Kaze FF, Kengne AP, Mambap AT, Halle MP, Mbanya D, Ashuntantang G Anemia in patients on chronic hemodialysis in Cameroon: prevalence, characteristics and management in low resources setting. Afr Health Sci 2015; 15:253–260.
16.	Delville M, Sabbah L, Girard D, Elie C, Manceau S, Piketty M, et al. Prevalence and predictors of early cardiovascular events after kidney transplantation: Evaluation of pre-transplant cardiovascular workup. PLoS ONE 2015; 10:e0131237.
17.	Eckardt KU, Scherhag A, Macdougall IC, Tsakiris D, Clyne N, Locatelli F, et al. Left ventricular geometry predicts cardiovascular outcomes associated with anemia correction in CKD. J Am Soc Nephrol 2009; 20:2651–2660.
18.	Li S, Foley RN, Collins AJ Anemia and cardiovascular disease, hospitalization, and stage renal disease, and death in older patients with chronic kidney disease. Int Urol Nephrol 2005; 37:395–402.
19.	Scialla JJ, Xie H, Rahman M, Anderson AH, Isakova T, Ojo A, et al. Fibroblast growth factor-23 and cardiovascular events in CKD, the chronic renal insufficiency cohort (CRIC) study investigators. J Am Soc Nephrol 2014; 25:349–360.
20.	Milovanova LY, Kozlovskaya LV, Milovanova SY, Kiyakbaev GG, Milovanov YS, Taranova MV Associations of fibroblast growth factor 23, soluble klotho, troponin 1 in CKD patients. Int Res J 2016; 9:65–69.
21.	Locatelli F, Aljama P, Bárány P, Canaud B, Carrera F, Eckardt KU, et al.; European Best Practice Guidelines Working Group. Revised European best practice guidelines for the management of anemia in patients with cronic renal failure. Nephrol Dial Transplant 2004; 19:ii2–ii45.
22.	Yarnoff BO, Hoerger TJ, Simpson SA, Pavkov ME, Burrows NR, Shrestha SS, Williams DE, Zhou X Cost-effectiveness of anemia treatment for persons with chronic kidney disease. PLoS ONE 2016; 11:e0157323.
23.	Schechter A, Gafter-Gvili A, Shepshelovich D, Rahamimov R, Gafter U, Mor E, et al. Post renal transplant anemia: severity, causes and their association with graft and patient survival. BMC Nephrol 2019; 20:51.
24.	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; 3:835–845.
25.	Molnar MZ, Czira M, Ambrus C, Szeifert L, Szentkiralyi A, Beko G, et al. Anemia is associated with mortality in kidney-transplanted patients – a prospective cohort study. Am J Transplant 2007; 7:818–824.
26.	Afzali B, Al-Khoury S, Shah N, Mikhail A, Covic A, Goldsmith D Anemia after renal transplantation. Am J Kidney Dis. 2006; 48:519–536.
27.	Chhabra D, Grafals M, Skaro AI, Parker M, Gallon L Impact of anemia after renal transplantation on patient and graft survival and on rate of acute rejection. Clin J Am Soc Nephrol 2008; 3:1168–1174.
28.	Vanrenterghem I Anemia after kidney transplantation. Transplantation 2009; 87:1265–1267.
29.	Winkelmayer WC, Chandraker A Pottransplantation anemia: management and rationale. CJASN 2008; 3(Suppl 2):49–55.
30.	Mitsnefes MM, Subat-Dezulovic M, Khoury PR, Goebel J, Strife CF Increasing incidence of post-kidney transplant anemia in children. Am J Transplant 2005; 5:1713–1718.
31.	Yorgin PD, Scandling JD, Belson A, Sanchez J, Alexander SR, Andreoni KA Late post-transplant anemia in adults renal transplant recipients. An under-recognized problem? Am J Transplant 2002; 2:429–435.
32.	Macdougall IC, Casadevall N, Locatelli F, Combe C, London GM, Di Paolo S, Kribben A Incidence of erythropoietin antibody-mediated pure red cell aplasia: the prospective immunogenicity surveillance registry (PRIMS). Nephrol Dial Transplant 2015; 30:451–460.
33.	Gafter-Gvili A, Cohen E, Avni T, Grossman A, Vidal L, Garty M, et al. Predicting the emergence of anemia – a large cohort study. Eur J Intern Med 2015; 26:338–343.
34.	Winkelmayer WC, Chandraker A, Alan Brookhart M, Kramar R, Sunder-Plassmann G A prospective study of anaemia and long-term outcomes in kidney transplant recipients. Nephrol Dial Transplant 2006; 21:3559–3566.
35.	Yorgin PD, Scandling JD, Belson A, Sanchez J, Alexander SR, Andreoni KA Late post-transplant anemia in adult renal transplant recipients. An under-recognized problem? Am J Transplant. 2002; 2:429–435.
36.	Hricik DE Anemia after kidney transplantation – is the incidence increasing? Am J Transplant. 2003; 3:771–772.
37.	Lorenz M, Kletzmayr J, Perschl A, Furrer A, Hörl WH, Sunder-Plassmann G Anemia and iron deficiencies among long-term renal transplant recipients. J Am Soc Nephrol. 2002; 13:794–797.
38.	Gafter-Gvili A, Gafter U Posttransplantation anemia in kidney transplant recipients. Acta Haematol 2019; 142:37–43.
39.	Shibagaki Y, Shetty A Anaemia is common after kidney transplantation, especially among African Americans. Nephrol Dial Transplant. 2004; 19:2368–2373.
40.	Babitt JL, Lin HY Mechanisms of anemia in CKD. J Am Soc Nephrol 2012; 23:1631–1634.
41.	Agarwal N, Prchal JT Anemia of chronic disease (anemia of inflammation). Acta Haematol 2009; 122:103–108.
42.	Grossman C, Dovrish Z, Koren-Morag N, Bornstein G, Leibowitz A Diabetes mellitus with normal renal function is associated with anaemia. Diab Metab Res Rev 2014; 30:291–296.
43.	Deray G, Heurtier A, Grimaldi A, Launay VV, Isnard BC Anemia and diabetes. Am J Nephrol 2004; 24:522–526.
44.	Ganz T, Nemeth E Iron sequestration and the anemia of inflammation. Semin Hematol 2009; 46:387–393.
45.	Kapitsinou PP, Liu Q, Unger TL, Rha J, Davidoff O, Keith B, et al. Hepatic HIF-2 regulates erythropoietic responses to hypoxia in renal anemia. Blood 2010; 116:3039–3048.
46.	Hu MC, Kuro-o M, Moe OW Renal and extra-renal actions of klotho. Semin Nephrol 2013; 33:118–129.
47.	Milovanova LY, Milovanov YS, Kudrjvceva DV, Markina MM, Milovanova SY, Kozlovskaya LV, et al. The role of morphogenetic proteins FGF-23, Klotho and glycoprotein sclerostin in the assessment of risk of cardiovascular diseases risk and CKD prognosis. Ter Arkh 2015; 6:10–16.
48.	Feldman HI, Israni RK, Yang W, Israni RK Hemoglobin variability and mortality among hemodialysis patients. J Am Soc Nephrol 2006; 17:583A.
49.	Yeun JY, Levine RA, Mantadilok V, Kaysen GA C-Reactive protein predicts all-cause and cardiovascular mortality in hemodialysis patients. Am J Kidney Dis 2000; 35:469–476.
50.	Awan AA, Winkelmayer WC, Murthy BV Anemia management and outcomes in kidney transplant recipients. Kidney 2019; 11:5.
51.	Mix TC, Kazmi W, Khan S, Ruthazer R, Rohrer R, Pereira BJ, Kausz AT Anemia: a continuing problem following kidney transplantation. Am J Transplant 2003; 3:1426–1433.
52.	Nadarajah L, Ashman N, Thuraisingham R, Barber C, Allard S, Green L Literature review of passenger lymphocyte syndrome following renal transplantation and two case reports. Am J Transplant 2013; 13:1594–1600.
53.	Etta PK Postrenal transplant anemia and pure red cell aplasia. Indian J Transplant 2019; 13:160–163.
54.	Casadevall N, Nataf J, Viron B, Kolta A, Kiladjian JJ, Martin-Dupont P Pure red-cell aplasia and antierythropoietin antibodies in patients treated with recombinant erythropoietin. N Engl J Med 2002; 346:469–475.
55.	Rossert J, Casadevall N, Eckardt KU Anti-erythropoietin antibodies and pure red cell aplasia. J Am Soc Nephrol 2004; 15:398–406.
56.	Chapter 1: diagnosis and evaluation of anemia in CKD. Kidney Int Suppl 2012; 2:288–291. Doi: 10.1038/kisup.2012.33
57.	Vellaboina B, Bonu R, Mukherjee T, Augustine R Antibody-mediated pure red cell aplasia after treatment with darbepoetin-alpha postrenal transplantation. Indian J Transplant 2019; 13:231–233.
58.	Thorpe R, Swanson SJ Assays for detecting and diagnosing antibody-mediated pure red cell aplasia (PRCA): an assessment of available procedures. Nephrol Dial Transplant 2005; 20(Suppl 4):iv16–iv22.
59.	Verhelst D, Rossert J, Casadevall N, Krüger A, Eckardt KU, Macdougall IC Treatment of erythropoietin-induced pure red cell aplasia: a retrospective study. Lancet 2004; 363:1768–1771.
60.	Sawada K, Fujishima N, Hirokawa M Acquired pure red cell aplasia: updated review of treatment. Br J Haematol 2008; 142:505–514.
61.	Hermanson T, Bennett CL, Macdougall IC Peginesatide for the treatment of anemia due to chronic kidney disease – an unfulfilled promise. Expert Opin Drug Saf 2016; 15:1421–1426.
62.	Garrigue V, Szwarc I, Giral M, Soulillou JP, Legendre C, Kreis H, et al. Influence of anemia on patient and graft survival after renal transplantation: results from the French DIVAT cohort. Transplantation. 2014; 97:168–175.
63.	Heinze G, Mitterbauer C, Regele H, Kramar R, Winkelmayer WC, Curhan GC, et al. Angiotensin-converting enzyme inhibitor or angiotensin II type 1 receptor antagonist therapy is associated with prolonged patient and graft survival after renal transplantation. J Am Soc Nephrol 2006; 17:889–899.
64.	Imoagene-Oyedeji AE, Rosas SE, Doyle AM, Goral S, Bloom RD Post-transplantation anemia at 12 months in kidney recipients treated with mycophenolate mofetil: risk factors and implications for mortality. J Am Soc Nephrol 2006; 17:3240–3247.
65.	Ichimaru N, Obi Y, Nakazawa S, Yamanaka K, Kakuta Y, Abe T, et al. Post-transplant anemia has strong influences on renal and patient outcomes in living kidney transplant patients. Transplant Proc. 2016; 48:878–883.
66.	Majernikova M, Rosenberger J, Prihodova L, Jarcuskova M, Roland R, Groothoff JW, et al. Posttransplant anemia as a prognostic factor of mortality in kidney transplant recipients. Biomed Res Int 2017; 2017:6987240.
67.	Rigatto C, Foley R, Jeffery J, Negrijn C, Tribula C, Parfrey P Electrocardiographic left ventricular hypertrophy in renal transplant recipients: prognostic value and impact of blood pressure and anemia. J Am Soc Nephrol 2003; 14:462–468.
68.	Rigatto C, Parfrey P, Foley R, Negrijn C, Tribula C, Jeffery J Congestive heart failure in renal transplant recipients: risk factors, outcomes, and relationship with ischemic heart disease. J Am Soc Nephrol 2002; 13:1084–1090.
69.	Choukroun G, Kamar N, Dussol B, Etienne I, Cassuto-Viguier E, Toupance O, et al. CAPRIT study Investigators. Correction of post-kidney transplant anemia reduces progression of allograft nephropathy. J Am Soc Nephrol 2012; 23:360–368.
70.	Chang WX, Arai S, Tamura Y, Kumagai T, Ota T, Shibata S, et al. Time-dependent risk factors associated with the decline of estimated GFR in CKD patients. Clin Exp Nephrol 2016; 20:58–70.
71.	Gheith O, Wafa E, Hassan N, Mostafa A, Sheashaa HA, Mahmoud K, et al. Does posttransplant anemia at 6 months affect long-term outcome of live-donor kidney transplantation? A single-center experience. Clin Exp Nephrol. 2009; 13:361–366.
72.	Kamar N, Rostaing L, Ignace S, Villar E Impact of post-transplant anemia on patient and graft survival rates after kidney transplantation: a meta-analysis. Clin Transplant. 2012; 26:461–469.
73.	Freiberg M, Chiurchiu C, Capra R, Eckhardt A, De La Fuente J, Douthat W, et al. Associated factors and clinical implications of post-transplant renal anemia. Medicina (B Aires) 2013; 73:136–140.
74.	Kovesdy CP, Trivedi BK, Kalantar-Zadeh K, Anderson JE Association of anemia with outcomes in men with moderate and severe chronic kidney disease. Kidney Int. 2006; 69:560–564.
75.	Gafter-Gvili A, Ayalon-Dangur I, Cooper L, Shochat T, Rahamimov R, Gafter U, et al. Post transplantation anemia in kidney transplant recipients: a retrospective cohort study. Medicine 2017; 96:e7735.
76.	Huang Z, Song T, Fu L, Rao Z, Zeng D, Qiu Y, et al. Post-renal transplantation anemia at 12 months: prevalence, risk factors, and impact on clinical outcomes. Int Urol Nephrol. 2015; 47:1577–1585.
77.	de Andrade LG, Abrao JM, Carvalho MF Anemia at one year is an independent risk factor of graft survival. Int Urol Nephrol 2012; 44:263–268.
78.	Park S, Kim YH, Kim YC, Yu Mi-Y, Lee JP, Han DJ, et al. Association between post-transplant red cell distribution width and prognosis of kidney transplant recipients. Sci Rep 2017; 7:13755.
79.	Schjelderup P, Dahle DO, Holdaas H, Mjøen G, Nordby G, Abedini S, Jardine A Anemia is a predictor of graft loss but not cardiovascular events and all-cause mortality in renal transplant recipients: follow-up data from the ALERT study. Clin Transpl 2013; 27:E636–E643.
80.	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; 80:903–909.
81.	Yorgin PD, Belson A, Sanchez J, Sanchez J, Al Uzri AY, Sarwal M, et al. Unexpectedly high prevalence of posttransplant anemia in pediatric and young adult renal transplant recipients. Am J Kidney Dis 2002; 40:1306–1318.
82.	Arias M, Hernández D, Guirado L, Campistol JM, Sánchez Plumed JA, Gómez E, et al. Clinical profile and post-transplant anaemia in renal transplant recipients restarting dialysis after a failed graft: changing trends between 2001 and 2009. Clin Kidney J 2013; 6:156–163.
83.	Alexandra TD, Nassim K, Olivier C, Laurence L, David R, Laure E, et al. Predictive factors of anemia within the first year post renal transplant. Transplantation 2005; 80:903–909.
84.	Budde K, Rath T, Kliem V Anemia control in kidney transplant recipients using once-monthly continuous erythropoietin receptor activator: a prospective, observational study. J Transplant. Available at: https://www.hindawi.com/journals/jtrans/2014/179705/
85.	Lim AKH, Arushi KA, Kanellis J Factors associated with anaemia in kidney transplant recipients in the first year after transplantation: a cross-sectional study. BMC Nephrol 2018; 19:252.
86.	Eisenga MF, Minovic I, Berger SP, Kootstra-Ros JE, van den Berg E, Riphagen IJ, et al. Iron deficiency, anemia, and mortality in renal transplant recipients. Transpl Int 2016; 29:1176–1183.
87.	Shah N, Al-Khoury S, Afzali B, Covic A, Roche A, Marsh J, et al. Posttransplantation anemia in adult renal allograft recipients: prevalence and predictors. Transplantation 2006; 81:1112–1118.
88.	Heinze G, Kainz A, Horl WH, Oberbauer R Mortality in renal transplant recipients given erythropoietins to increase hemoglobin concentration: cohort study. BMJ. 2009; 339:b4018.
89.	Winkelmayer WC, Lorenz M, Kramar R, Horl WH, Sunder-Plassmann G Percentage of hypochromic red blood cells is an independent risk factor for mortality in kidney transplant recipients. Am J Transplant 2004; 4:2075–2081.
90.	Karakus S, Kanbay M, Koseoglu HK, Colak T, Haberal M Causes of anemia in renal transplant recipients. Transplant Proc 2004; 36:164–165.
91.	Mahmud SN, Aziz R, Ahmed E, Akhtar F, Zafar MN, Naqvi A, Rizvi A Anemia characteristics after renal transplantation. Transplant Proc 2002; 34:2428.
92.	Allen LA, Felker GM, Mehra MR, Chiong JR, Dunlap SH, Ghali JK, et al. Validation and potential mechanisms of red cell distribution width as a prognostic marker in heart failure. J Card Fail 2010; 16:230–238.
93.	Dabbah S, Hammerman H, Markiewicz W and Aronson D Relation between red cell distribution width and clinical outcomes after acute myocardial infarction. Am J Cardiol 2010; 105:312–317.
94.	Felker GM, Allen LA, Pocock SJ, Shaw LK, McMurray JJ, Pfeffer MA, et al., CHARM Investigators. Red cell distribution width as a novel prognostic marker in heart failure: data from the CHARM Program and the Duke Databank. J Am Coll Cardiol 2007; 50:40–47.
95.	Forhecz Z, Gombos T, Borgulya G, Pozsonyi Z, Prohászka Z, Jánoskuti L Red cell distribution width in heart failure: prediction of clinical events and relationship with markers of ineffective erythropoiesis, inflammation, renal function, and nutritional state. Am Heart J 2009; 158:659–666.
96.	Oh HJ, Park JT, Kim JK, Yoo DE, Kim SJ, Han SH, et al. Red blood cell distribution width is an independent predictor of mortality in acute kidney injury patients treated with continuous renal replacement therapy. Nephrol Dial Transplant 2012; 27:589–594.
97.	Yoon HE, Kim SJ, Hwang HS, Chung S, Yang CW, Shin SJ Progressive rise in red blood cell distribution width predicts mortality and cardiovascular events in end-stage renal disease patients. PLoS ONE 2015; 10:e0126272.
98.	Chen PC, Sung FC, Chien KL, Hsu HC, Su TC, Lee YT Red blood cell distribution width and risk of cardiovascular events and mortality in a community cohort in Taiwan. Am J Epidemiol 2010; 171:214–220.
99.	Perlstein TS, Weuve J, Pfeffer MA and Beckman JA Red blood cell distribution width and mortality risk in a community-based prospective cohort. Arch Intern Med 2009; 169:588–594.
100.	Mucsi I, Ujszaszi A, Czira ME, Novak M and Molnar MZ Red cell distribution width is associated with mortality in kidney transplant recipients. Int Urol Nephrol 2014; 46:641–651.
101.	Ujszaszi A, Molnar MZ, Czira ME, Novak M and Mucsi I Renal function is independently associated with red cell distribution width in kidney transplant recipients: a potential new auxiliary parameter for the clinical evaluation of patients with chronic kidney disease. Br J Haematol 2013; 161:715–725.
102.	Uyarel H, Ergelen M, Cicek G, Kaya MG, Ayhan E, Turkkan C, et al. Red cell distribution width as a novel prognostic marker in patients undergoing primary angioplasty for acute myocardial infarction. Coron Artery Dis 2011; 22:138–144.
103.	Warwick R, Mediratta N, Shaw M, McShane J, Pullan M, Chalmers J, Poullis M Red cell distribution width and coronary artery bypass surgery. Eur J Cardiothorac Surg 2013; 43:1165–1169.
104.	Huang YL, Hu ZD, Liu SJ, Sun Y, Qin Q, Qin BD, et al. Prognostic value of red blood cell distribution width for patients with heart failure: a systematic review and meta-analysis of cohort studies. PLoS ONE 2014; 9:e104861.
105.	Su C, Liao LZ, Song Y, Xu ZW, Mei WY The role of red blood cell distribution width in mortality and cardiovascular risk among patients with coronary artery diseases: a systematic review and meta-analysis. J Thorac Dis 2014; 6:1429–1440.
106.	Bujak K, Wasilewski J, Osadnik T, Jonczyk S, Kołodziejska A, Gierlotka M, Gąsior M The prognostic role of red blood cell distribution width in coronary artery disease: a review of the pathophysiology. Dis Markers 2015; 2015:824624.
107.	Moal V, Brunet P, Dou L, Morange S, Sampol J, Berland Y Impaired expression of glycoproteins on resting and stimulated platelets in uraemic patients. Nephrol Dial Transplant 2003; 18:1834–1841.
108.	Patel KV, Ferrucci L, Ershler WB, Longo DL, Guralnik JM Red blood cell distribution width and the risk of death in middle-aged and older adults. Arch Intern Med 2009; 169:515–523.
109.	Cheng CK, Chan J, Cembrowski GS, van Assendelft OW Complete blood count reference interval diagrams derived from NHANES III: stratification by age, sex, and race. Lab Hematol 2004; 10:42–53.
110.	KDIGO Anaemia Work Group. KDIGO clinical practice guideline for anemia in chronic kidney disease. Kidney Int 2012; 2(Suppl 2):279–335.
111.	Rozen-Zvi B, Gafter-Gvili A, Zingerman B, Levy-Drummer RS, Levy L, Mor E, et al. Intravenous iron supplementation after kidney transplantation. Clin Transpl. 2012; 26:608–614.
112.	Mudge DW, Tan KS, Miles R, Johnson DW, Badve SV, Campbell SB, et al. A randomized controlled trial of intravenous or oral iron for posttransplant anemia in kidney transplantation. Transplantation 2012; 93:822–826.
113.	Shepshelovich D, Rozen-Zvi B, Avni T, Gafter U, Gafter-Gvili A Intravenous versus oral iron supplementation for the treatment of anemia in CKD: an updated systematic review and meta-analysis. Am J Kidney Dis 2016; 68:677–690.
114.	Avni T, Bieber A, Grossman A, Green H, Leibovici L, Gafter-Gvili A The safety of intravenous iron preparations: systematic review and meta-analysis. Mayo Clin Proc. 2015; 90:12–23.
115.	Kliger AS, Foley RN, Goldfarb DS, Goldstein SL, Johansen K, Singh A, et al. KDOQI US commentary on the 2012 KDIGO Clinical Practice Guideline for Anemia in CKD. Am J Kidney Dis 2013; 62:849–859.
116.	Cassis P, Gallon L, Benigni A, Mister M, Pezzotta A, Solini S, et al. Erythropoietin, but not the correction of anemia alone, protects from chronic kidney allograft injury. Kidney Int 2012; 81:903–918.
117.	Diskin CJ, Stokes TJ, Dansby LM, Radcliff L, Carter TB Beyond anemia: the clinical impact of the physiologic effects of erythropoietin. Semin Dial 2008; 21:447–454.
118.	Purroy C, Fairchild RL, Tanaka T, Baldwin WM III, Manrique J, Madsen JC, et al. Erythropoietin receptor-mediated molecular crosstalk promotes T cell immunoregulation and transplant survival. J Am Soc Nephrol 2017; 28:2377–2392.
119.	Singh AK, Szczech L, Tang KL, Barnhart H, Sapp S, Wolfson M, et al., CHOIR Investigators. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med 2006; 355:2085–2098.
120.	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; 361:2019–2032.
121.	Drüeke TB, Locatelli F, Clyne N, Eckardt KU, Macdougall IC, Tsakiris D, et al. CREATE Investigators. Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med 2006; 355:2071–2084.
122.	KDOQI, National Kidney Foundation. IV. Clinical practice recommendations for anemia in chronic kidney disease in transplant recipients. Am J Kidney Dis 2006; 47:S109–S116.
123.	Kasiske BL, Zeier MG, Chapman JR, Craig JC, Ekberg H, Garvey CA, et al. KDIGO clinical practice guideline for the care of kidney transplant recipients: a summary. Kidney Int 2010; 77:299–311.
124.	Tsujita M, Kosugi T, Goto N, Futamura K, Nishihira M, Okada M, et al. The effect of maintaining high hemoglobin levels on long-term kidney function in kidney transplant recipients: a randomized controlled trial. Nephrol Dial Transplant 2019; 4:1409–1416.
125.	Carson JL, Guyatt G, Heddle NM, Grossman BJ, Cohn CS, Fung MK, et al. Clinical practice guidelines from the AABB red blood cell transfusion thresholds and storage. JAMA 2016; 316:2025–2035.