Journal of Nephrology

https://doi.org/10.1007/s40620-019-00680-5

REVIEW

Red cell transfusion in chronic kidney disease in the United States

in the current era of erythropoiesis stimulating agents
Nicole Brenner1 · Anuhya Kommalapati2 · Muhammad Ahsan1 · Anirban Ganguli1

Received: 8 June 2019 / Accepted: 24 November 2019

© Italian Society of Nephrology 2019

Abstract
Anemia is a major complication of chronic kidney disease (CKD) that leads to many symptoms of this disease and worsens
cardiovascular health. Treatment of this condition was revolutionized three decades ago by the commercial availability of
recombinant human erythropoietin which held the promise of completely eliminating the need for red blood cell transfusion
(RBCT). Despite specific therapy now available for anemia in CKD, clinical data accumulated in the last 2 decades suggests
that there is a continued need for RBCT, which, we surmise, is due to underutilization of Erythropoietin Stimulating Agents
(ESA) or clinical settings such as active bleed, bone marrow resistance such as myelofibrosis or infections where ESAs
are ineffective. The purpose of this narrative review is to highlight the adverse effects and summarize the current patterns
of RBCT use in all stages of CKD while elaborating on the clinical characteristics of patients that increases their risks of
transfusion exposure. We discuss, briefly, salient features of the pathophysiology of anemia in CKD and its contemporary
therapies while presenting our perspectives on how to optimize transfusion strategies without compromising patient safety.

Keywords  Red cell transfusion · Chronic kidney disease · Anemia

Introduction management of anemia in CKD continues to evolve in light

Anemia of chronic kidney disease (CKD)results, mainly,
from inadequate secretion of the hormone erythropoietin
(EPO) from the renal parenchyma [1–3]. Commercial avail-
ability of recombinant human erythropoietin(rHuEPO) since
the late 1980s revolutionized management of this condition
by mitigating symptoms of severe anemia, promoting a bet-
ter quality of life and reducing the need for chronic red cell
transfusion which can cause blood borne infections, iron-
overload, circulatory overload or allosensitization [4–7]. As
The data reported here have been supplied by the United States
Renal Data System (USRDS). The interpretation and reporting
of these data are the responsibility of the author(s) and in no way
should be seen as an official policy or interpretation of the U.S.
government.
* Anirban Ganguli
ranagang77@gmail.com
1
Division of Nephrology, Department of Medicine,
Georgetown University/Washington Hospital Center, 110
Irving Street, Suite 2A 50, Washington, DC, NW 20010,
USA
2 therapeutic nihilism [14]. In this narrative review, we chart
University of South Carolina, Columbia, SC, USA
of newer therapies, clinical practice guidelines reflect mod-
est hemoglobin goals that can avert blood transfusions while
limiting Erythropoiesis Stimulating Agents (ESA) exposure
given its numerous side effects [6, 8–10].
Despite remarkable progress in anemia management in
CKD in the last 3 decades, current data indicate that red
blood cell transfusion (RBCT)incident rates in the US CKD
population is almost twice as high (11.7–16.6%) as com-
pared to the general population (5.7%) [10–13]. It is reassur-
ing, however, that RBCT rates in the CKD population have
been declining in the last decade [10]. Current patterns of
RBCT use in CKD could indicate many possibilities such
as provider under-utilization of specific therapies or high
incidence of coexisting clinical conditions that attenuate the
beneficial response of ESA. Even though current regulatory
policies in the US highlight physician and administrative
concerns over adverse effects of ESA unmasked in rand-
omized trials designed to normalize hemoglobin levels in
CKD, many of the poor outcomes associated with ESAs
may be confounded by coexisting clinical conditions such
as inflammation or malignancy that could independently
affect survival in CKD, highlighting the need to avoid

13
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the epidemiology of red-cell transfusion in both dialysis
dependent and non-dialysis dependent CKD in the US over
the last decade while identifying the prevalence of specific
risk factors that predispose to ESA resistance. We will also
briefly touch upon some of the recent reimbursement policy
changes in the US over the last decade which may poten-
tially contribute to time-trends in RBCT incidence rates in
CKD. Finally, we will present an evidence-base for current
blood transfusion thresholds in CKD and formulate a clini-
cal strategy to limit the use of this precious resource without
compromising patient safety.
Pathophysiology of anemia in chronic
kidney disease and clinical implications
Anemia (hemoglobin less than 12 g/dL in males or less than
11 g/dL in females) is a major complication of CKD and
increases in incidence with severity of disease process [15].
It is almost universal when patients reach the stage of end
stage renal disease [10]. Anemia substantially contributes
to the symptom burden in CKD such as fatigue, shortness
of breath, insomnia or mental acuity translating into poor
quality of life and functional capacity [6, 16]. It also contrib-
utes to the problem of left ventricular hypertrophy (LVH) in
CKD, which is considered an important contributor to car-
diovascular morbidity and mortality in CKD [17]. Despite
observational data demonstrating strong associations of
anemia with CKD related morbidity, interventional stud-
ies show only limited improvement in LVH and marginal
benefits on cardiovascular events of mortality with Hb cor-
rection beyond 10 g/dL [17–19]. Regardless of hard clinical
outcomes, anemia in CKD is associated with increased use
of health-care resources along with frequent hospitalizations
and emergency visits [12].
Renal anemia typically starts as normochromic and nor-
mocytic but later may become hypochromic and microcytic
especially due to iron deficiency [1]. This results from a
complex interplay of many factors that lead to either reduced
bone marrow RBC production or decreased RBC survival [1,
2]. The main mechanism appears to be reduced bone-marrow
RBC production due to the absolute or relative deficiency of
EPOthat is primarily produced by the renal parenchyma [1].
EPO is the key hormone that ensures the survival and prolif-
eration of RBC precursors [2]. Coexisting causes of anemia
in CKD could be either nutritional deficiencies (iron, folate
or vitamin B12) or systemic inflammation which results in
a block in iron transfer from either duodenal enterocytes or
reticulo-endothelial cells to RBC precursors [1].
13
Journal of Nephrology
A brief over‑view of anemia management
in CKD
The key to managing anemia in CKD is to diagnose and
treat the underlying mechanism. Since EPO deficiency
(relative or absolute) is the prime cause of anemia in
CKD, the mainstay of therapy is ESA, which is currently
available in three chemical forms-epoetin alfa, methoxy
polyethylene glycol-epoetin beta and darbepoetin alfa [6].
Overall, ESAs are very effective in the chronic setting
and the pivotal trial by Eschbach et al., noted an improve-
ment of hematocrit from a baseline of around 22–35% in
12 weeks, resulting in freedom from red-cell transfusion
within 2 months and resolution of iron overload within
6 months of starting therapy [4]. Numerous randomized
trials following the Eschbach trial echoed similar results
with a recent metaanalysis showing definitive evidence
that ESA reduces transfusion dependence, even though
their effects on patient centered outcomes and mortality
remains unproven [20, 21].
A meta-analysis of all randomized trials using ESAs till
date showed that at Hb target of around 10 g/dL, the ben-
efits of ESA therapy appeared to peak and adverse effects
were minimal [20]. The KDIGO-2012, NICE and ERBP
all converge on this minimum Hb target for patients on
ESA in their respective consensus statements [6, 22, 23].
Adverse effects from ESA include risk of hypertension,
thrombosis of vascular access, stroke, myocardial infarc-
tion and even death and appeared to increase with dose
regimens that attempted to target normal hemoglobin lev-
els [8, 9, 24]. The adverse events seen with higher hemo-
globin targets appear to be ESA dose-related and not on
achieved hematocrit indicating need to limit ESA expo-
sure to minimum [25]. To generalize, currently accepted
end-points of anemia therapy in CKD are improvement
in physical symptoms while limiting harms of therapy.
In accordance with this principle, the Kidney Disease
Improving Global Outcomes initiative (KDIGO-2012)
recommends a target Hb in the range of 10–11.5 g/dL [6].
The European(ERBP-2013) and the UK(NICE-2015) prac-
tice guidelines also converge on the same evidence-base
as mentioned above although the recommended Hb goal
range is 10–12 g/dL, with advice to individualize target
based on patient comorbidities such as diabetes mellitus,
stroke, ischemic heart disease, cancer or those hypore-
sponsive to ESA therapy [22, 23].
Journal of Nephrology
Adverse effects of red blood cell transfusion
in CKD
Regardless of the current trends in blood transfusion prac-
tices in CKD, the benchmark of good anemia management
policies in the era of ESA use is to limit the use of red
cell transfusions given multiple adverse effects associated
with this therapy (Fig. 1). While most of the complications
from RBCT are similar to the general population, some of
these may be unique to the CKD population. The risk of
transfusion transmitted infection is overall very minimal
in developed countries such as the US due to thorough
screening policies of the donor and donated blood [26].
For instance, the current risk of transmission of HIV or
Hepatitis C infection is less than 1 in 1 million [27]. A
risk of CMV infection especially exists in immunocom-
promised, transplant patients that can be minimized with
leucoreduced red-cell transfusion [28]. Sepsis from gram
negative bacteria is a rare complication of a red-cell trans-
fusion that tends to increase in frequency as RBC storage
time increases [7, 26]. Recently, transfusion-transmitted
babesiosis has been reported as a new form of transfusion
related infection with high mortality rates of 15–20% [29].
Non-infectious complications of red cell transfusions
include hemolytic transfusion reactions, febrile non-hemo-
lytic transfusion reactions, allergic reactions, transfusion
related lung injury (TRALI), transfusion associated circu-
latory overload (TACO), post transfusion purpura, transfu-
sion associated graft-versus-host disease, hyperkalemia,
citrate toxicity (in massive transfusions), iron overload (in
Fig. 1  Schematic representation of the adverse effects of red cell transfusion (RBCT) in Chronic Kidney Disease (CKD)
chronic transfusion dependence) and alloimmunization to
RBC or HLA antigens (if contaminating WBCs are pre-
sent) [7, 26]. Some of the complications such as TACO or
hyperkalemia are believed to be more common in CKD,
especially dialysis patients [7].
While RBC alloimmunization can increase risk of
delayed hemolytic transfusion reaction, antibodies to HLA
antigens (especially Class I) can reduce chances of success-
ful renal transplantation [7]. A recent systematic review of
180 studies from 1984 to 2011 showed that alloimmuni-
zation was significantly higher in CKD patients receiving
a pre-transplant RBCT and risk increased with increased
number of transfused units [30]. The highest risk for alloim-
munization with RBCT seemed to be in multi-parous women
or those with previous transplantation [31]. The downstream
harms of alloimmunization are increased propensity to form
donor specific antibodies, elevated panel reactive antibod-
ies, increased wait-times for renal transplantation and higher
risks for graft rejection [30].
Apart from adverse effects, RBCT is less cost-effective
than ESAs in treating anemia of CKD, as shown in a simu-
lation study on a cohort of Medicare ESRD patients from
1995 to 2004 receiving either ESA or RBCT for anemia
in CKD, where the incremental cost-effectiveness ratio
(ICER) of ESAs over RBCT was only $873 per quality-
adjusted life-years (QALYs)[32]. Similar incremental ben-
efits have been reported with ESA over RBCT in different
countries [33, 34]. Furthermore, patient-centered research
on patient’s preference for different treatment options in ane-
mia of CKD showed that patients were willing to trade off a
6% increase in risk for medication-related adverse effect of
13

Fig. 2  Relative bother estimates
of different forms of adverse
effects associated with red
cell transfusion as perceived
by CKD patients during a
“Discrete Choice Experiment”
survey. Greater the score more
bothersome is the item to the
patient. (Reproduced with
permission from [35])
heart attack to avoid blood transfusion and that transfusion-
related lung injury was the most concerning side effect for
patients(Fig. 2) [35]. Finally, it is necessary to avoid blood
transfusion as much as possible since human blood is a pre-
cious resource.
Trends in red cell transfusions in CKD
since the discovery of ESA up to the present
period
Effective use of ESA in anemic CKD patients should essen-
tially reduce the need for RBCT to that of the general popu-
lation. Such optimism was generated soon after rHuEPO
introduction in the 1990s that led to dramatic improvement
in mean hemoglobin levels of CKD patients and a drop in
inpatient and outpatient RBCT incidence rates to as low
as 7.5% per quarter in 2000 [36]. However, following the
adverse events reporting of ESA in major trials of hemo-
globin normalization during the late 1990s and 2000s, reg-
istry data showed that the mean dosing of ESA used along
with achieved hemoglobin dropped in the early 2010, espe-
cially within the US hemodialysis population [37]. Around
this time, policy-makers brought significant changes in the
structure of medical reimbursement for Medicare dialysis
patients that appeared to discourage liberal use of ESA [38].
The new policy, which was termed as the bundled prospec-
tive payment system (PPS), disallowed separate billing for
medications such as ESAs while providing a bundled pay-
ment to all dialysis units to meet the overall cost of all drugs
administered during dialysis (including ESA), blood tests
and other supplies per dialysis session [38]. Additionally, the
FDA issued a black box on ESA in 2011 warning prescrib-
ers about potential risks of adverse events with ESA ther-
apy to Hb level of greater than 11 g/dL while emphasizing
that there is no safe hemoglobin target level, ESA dose, or
13
Journal of Nephrology
dosing strategy that mitigates these risks [39]. Additionally,
the FDA recommended individualization of hemoglobin
goals with the broad goal of avoiding blood transfusions
[39]. Taking a cue from FDA black-box warning, the Center
for Medicare and Medicaid Services (CMS) announced in
2013 that it was removing its anemia performance metric
of maintaining Hb level of at least 10 g/dL from its Quality
Incentive Program (QIP) for dialysis programs [40].
The effects of such monumental policy changes became
evident within 2 years of implementation of the PPS when
the Governmental Accountability Office noted a 23% reduc-
tion in the use of medications included as a part of bundled
payment during dialysis that was largely driven by a 30%
decline in ESA use from the third quarter of 2010 through
the end of 2011 [41]. In this backdrop of fall in ESA use,
comparative observational data from US dialysis facilities
around this time showed an increase in the prevalence of
patients with Hb levels < 10 g/dL from 6% in 2007 to 11% in
2011 that seemed to result in a 28% greater risk of red-cell
transfusion, especially in patients with Hb levels less than
10 g/dL for last 3 months [42].The impact was felt similarly
in both commercially insured and state- funded(Medicare)
chronically dialyzed patients as noted in an observational
study that showed that the proportion of chronic dialysis
patients who received at least one RBC transfusion rose
2.4% in January of 2007 to 3.0% in January 2009 and 3.4% in
January of 2012 as shown in Fig. 3 [43]. Similar trends were
seen in an observational study on non-dialysis CKD(ND-
CKD) patients between the time-period 2006-2015 that
analyzed anemia practice in the US through the watershed
periods of October 2009(TREAT study publication) and
June 2011(USFDA safety warning on ESA use) [44]. The
authors showed a decline in the adjusted probabilities of pre-
scribing ESA by 31% in the post-TREAT period [odds ratio
(OR) = 0.69, 95% confidence interval (CI) 0.67–0.71] and
59% (OR = 0.41, 95% CI 0.40, 0.42) in post-FDA warning
Journal of Nephrology
Fig. 3  Monthly percentage of chronic dialysis patients in the US
receiving RBC transfusion in commercial insurance and Medicare
based (government-funded) populations from 2007 through 2012
Adapted from Cappell KA, Shreay S, Cao Z, Varker HV, Paoli CJ,
Gitlin M. Red blood cell (RBC) transfusion rates among US chronic
dialysis patients during changes to Medicare end-stage renal disease
(ESRD) reimbursement systems and erythropoiesis stimulating agent
(ESA) labels. BMC Nephrol. 2014; 15:116
periods compared to pre-TREAT period with increased prob-
abilities of RBCT use during the post-TREAT and post-FDA
warning periods of 14% (OR = 1.14, 95% CI 1.06–1.23) and
31% (OR = 1.31, 95% CI 1.22–1.39), respectively [44]. It
is possible that this change in anemia practice may have
specifically impacted the US since trans-national studies
during this time period demonstrated a consistent pattern
of decreased ESA doses and falling Hb levels in the US as
compared to other countries [45]. Other potential factors
responsible for this trend, especially in ND-CKD patients,
could be absence of a lower Hb limit to start ESA as per
the KDIGO guidelines [6]. In recent years RBCT rates in
ESRD patients appears to have been reduced. The recently
compiled USRDS-2018 datasheet notes that the percent of
HD patients receiving > 1 RBCT declined from 23.9% in
2012 to 16.6% in 2016 even though mean Hb levels continue
to trend down [10].
Clinical characteristics of CKD patients
needing blood transfusion in the present
period
While it is quite possible that underutilization of ESAs may
be contributory to high RBCT transfusion rates in CKD,
one of the primary reasons of transfusion-dependence in
CKD is the lack of response to ESA or contra-indications
to ESA therapy such as ongoing malignancy or previous
stroke [6]. The original ESA study of Eschbach noted ESA
non-responders to have complicated causes of anemia,
including myelofibrosis, osteitis fibrosa, osteomyelitis, acute
and chronic blood losses [4]. The KDIGO-2012 guidelines
broadly define ESA hyporesponsiveness as the absence
of an increase in Hb concentration from baseline after at
least a month of appropriate weight-based doses and rec-
ommendruling out medication non-compliance, nutritional
(iron, folate, Vit B12) deficiency, underdialysis(in ESRD
patients), medications (angiotensin-converting enzyme
inhibitors or angiotensin-receptor blockers), severe hyper-
parathyroidism, inflammation or pure red cell aplasia [6].
While epidemiological data on ESA hypo-responsiveness in
non-dialysis CKD is scarce, a recent observational study in
the post-PPS era amongst a large cohort of US hemodialysis
patients found an overall prevalence of 12.5% with majority
of patients (61.3%) regaining ESA responsiveness within
4 months (termed as “acute”) [46]. The study noted that ESA
hyporesponsiveness was more prevalent in young female
patients, those with Afro-American ethnicity, in patients
using central venous catheter as dialysis access, those with
greater co-morbidity burden, those with coexisting non-renal
causes of anemia and those receiving antibiotic therapy in
the last 90 days [46]. The frequency of monthly RBCT was
fivefold higher in “acute” and sevenfold higher in “chronic”
(> 4 months) ESA hyporesponsive patients with significantly
higher risk of mortality than ESA responders [46].
Another reason for RBCT in CKD could be a target
Hb driven approach or acute illnesses. This was shown in
a Canadian study on incident outpatient dialysis patients
where the most frequent reason of RBCT was a low Hb
value (92%) [47]. Less common indications include gastro-
intestinal bleeding (9.9%) and surgical blood loss (8.6%)
[47]. Of note, only 4.5% of patients had symptoms of severe
anemia necessitating a RBCT [47]. The authors identified
inpatient initiation of dialysis as a major risk factor for
transfusion, which, they believed, indicated poor quality of
medical care and systemic inflammation [44]. There is pau-
city of data on clinical characteristics of non-dialysis CKD
patients (ND-CKD) receiving RBCT. However, two recent
observational studies from different health-care systems
identified inpatient setting, peripheral vascular disease and
recent hospitalization as major risk factors for RBCT [48,
49]. The possibility of underutilization of existing therapies
was suggested as a potential explanation for RBCT in CKD
since transfusion rates appeared to be highest in patients not
receiving either iron supplementation or ESA [49]. None of
the studies mention whether a nephrologist was involved in
anemia management of these patients [48, 49].
Given the absence of rigorous trials on transfusion prac-
tices in CKD and the possibility of residual confounders in
observational studies, prescriber preferences could provide
additional insight to decision-making process in RBCT. In a
choice-based conjoint survey of generalists and hospitalists
in the Veteran Administration System on RBCT decision
in anemic dialysis dependent CKD patients (Fig. 4), abso-
lute Hb level was the single most important consideration
13

Fig. 4  Relative bother estimates of different forms of adverse effects
associated with red cell transfusion as perceived by CKD patients
during a “Discrete Choice Experiment” survey. Greater the score
more bothersome is the item to the patient. (Reproduced with permis-
sion from [35])
(29%), followed by patient’s functional status (16%) and
cardiovascular comorbidities (12%) [50]. Transplant eligi-
bility explained only 5% of decision-making process even
though nephrologists were 5 times more likely to realize
the importance of this issue than non-nephrologists [50].
Of note, it has been shown in a randomized study that the
impact of higher hemoglobin target is a reduction in RBCT
rates [51]. In a randomized trial on incident hemodialysis
patients(n = 596), RBCT rates in group with high Hb target
range of 13.5–14.5 g/dL were significantly lower than the
group in which Hb target range was set between 9.5 and
11.5 g/dL (0.26 vs 0.66 units per year) [51].
Transfusion thresholds and implications
on survival in general population and CKD
There is a paucity of randomized studies looking into trans-
fusion thresholds specifically in CKD patients. However,
data on RBCT in the acute settings is available in general
population studies that seem to dichotomize this decision-
making process to either “liberal” (hence higher Hb) thresh-
olds or “restrictive” (hence lower Hb) transfusion goals. A
recent meta-analysis pooled data from 31 trials (n = 12,587)
that included patients from different specialties (surgery
and critical care) classified transfusion policies as “liberal”
(varying Hb thresholds) or “restrictive” thresholds (either
Hb < 7 g/dL or < 8 g/dL or even 9 g/dL) [52]. The authors
found no difference in 30-day mortality, stroke, thrombo-
embolism or cardiac events between the two groups while
the “restrictive” group was able to avoid transfusion in 43%
of cases [51]. The results of this meta-analysis could be
13
Journal of Nephrology
generalizable to renal patients since none of the individual
studies excluded CKD patients [52]. One of the included tri-
als in the meta-analysis specifically included CKD patients
(defined by Serum Creatinine > 2.0 mg/dl) to study the effect
of different transfusion threshold in patients undergoing hip
surgery [53].
Strategies to optimize hemoglobin target
and minimize transfusion burden in CKD
Given the paucity of randomized trials addressing the ques-
tion of a safe blood transfusion threshold in CKD, most
recommendations are based on critical appraisal of exist-
ing literature and expert opinion. The KDIGO-2012 anemia
guidelines give comprehensive recommendations on this
topic in CKD patients using the GRADE methodology [6,
54]. Additionally, the American Association of Blood Banks
(AABB) guidelines published in 2016 and endorsed by the
American Society of Hematology give general recommen-
dations on transfusion thresholds that are applicable in all
patients [55]. We present these guidelines in Table 1. Addi-
tionally, we recommend the following strategies:
1. Whenever possible, continue to use ESA with or without
intravenous iron in CKD patients when they are acutely
ill and admitted in hospital unless there are contraindica-
tions to using these agents.
2. Use less invasive procedures when CKD patients are
hospitalized. In one study, use of trans-radial access for
cardiac catheterization led to lesser need for blood trans-
fusion 48 h post-surgery [56].
3. In every CKD patient triage the decision for blood-trans-
fusion based on whether the patient is a future candidate
for renal transplantation.
4. Individualize transfusion need based on acuity of situa-
tion- for instance threshold of transfusion in acute blood
loss may be higher than chronic asymptomatic anemia.
5. Patients with anemia in the setting of acute cardiovas-
cular conditions such as acute myocardial infarction or
postcardiac surgery may need a higher than usual trans-
fusion threshold.
Conclusions
In summary, our narrative review gives a broad outline of
the complex pathophysiology of anemia in CKD in order to
highlight the limitations of current anemia therapies while
explaining why it is impossible to avoid or avert the use of
RBCT in CKD. Notwithstanding the issue of ESA hypore-
sponsiveness, underutilization of ESA is a key remediable
factor identified in observational studies looking into the
Journal of Nephrology

Table 1  General and specific recommendation on the use of Red Cell Transfusion. Adapted from the AABB-2016 and the KDIGO-2012 guide-
lines [6, 55]

Strength of recommendation using

GRADE system [54]

AABB-2016 general recommendations on RBCT thresholds

 Hemodynamically stable adult inpatients, transfuse if Hb ≤ 7 gm/dL 1B
 ICU hemodynamically stable adult patients, transfuse if Hb ≤ 7 gm/dL 1A
 Postoperative orthopedic or cardiac surgery patients, transfuse if Hb ≤ 8 gm/dL or with symp- 1B
toms
 Cardiovascular Disease, transfuse if Hb ≤ 8 gm/dL or with symptoms 1B
 In acute coronary Syndrome the AABB does not recommend for or against a liberal or restric- Uncertain, very low-quality evidence
tive RBC transfusion strategy
 In all patients transfusion should be guided by symptoms as well as by Hb level 2C
KDIGO-2012 recommendations on indications of RBCT in CKD
 4.1.1   “…we recommend avoiding, when possible, red cell transfusions to minimize the general 1B
risks related to their use.”
 4.1.2   “In patients eligible for organ transplantation, we specifically recommend avoiding, when pos- 1C
sible, red cell transfusions to minimize the risk of allosensitization.”
 4.1.3   “…. benefits of red cell transfusions may outweigh the risks in patients in whom 2C
  ESA therapy is ineffective (e.g., hemoglobinopathies,   bone marrow failure, ESA resistance)
  The risks of ESA therapy may outweigh its benefits (e.g., previous or current malignancy,
previous stroke)”
 4.1.4   “We suggest that the decision to transfuse a CKD patient with non-acute anemia should not 2C
be based on any arbitrary Hb threshold, but should be determined by the occurrence of
symptoms caused by anemia.”

CKD chronic kidney disease, ESA erythropoiesis stimulating agents, GRADE grading of recommendations assessment, development and evalua-
tion, Hb hemoglobin, KDIGO kidney disease improving global outcomes RBCT red blood cell transfusion

issue of continued use of RBCT in the CKD population.
We think that an effective strategy aimed at reducing RBCT
rates in CKD without compromising patient safety is to
focus on hemoglobin optimization in high risk populations
such as inpatient CKD, recent dialysis starts or those with
multiple co-morbidities. Data from randomized studies in
general population can be used to justify a restrictive RBC
transfusion policy in acutely ill CKD patients, without com-
promising patient safety. A major limitation in current lit-
erature is the lack of randomized trials looking at long term
clinical outcomes and cost-efficacy of different transfusion
strategies in the CKD population.
Acknowledgements  We wish to sincerely thank Drs Elizabeth Adams-
Eilers and Dr Robert P. Eilers for their valuable comments and sugges-
tions in preparing this manuscript.
Compliance with ethical standards  5. Johansen KL, Finkelstein FO, Revicki DA, Evans C, Wan S, Git-
Conflict of interest The authors declare that they have no potential
conflicts of interest in preparation of this manuscript.
Ethical approval  The authors of this article declare that they have no
potential conflicts of interests in the preparation or presentation of
the contents of this manuscript. During the process of preparing this
article, the authors did not involve in research that included human
participants and/or animals.
Informed consent  No informed consent was taken since this article
is a narrative review of literature and not a primary research data on
human subjects
References
1. Babitt JL, Lin H (2012) Mechanisms of anemia in CKD. J Am Soc
Nephrol 23(10):1631–1634
2. Eschbach JW (1989) The anemia of chronic renal failure: patho-
physiology and the effects of recombinant erythropoietin. Kidney
Int 35(1):134–148
3. Erslev A (1953) Humoral regulation of red cell production. Blood
8:349–357
4. Eschbach JW, Abdulhadi MH, Browne JK, Delano BG, Down-
ing MR, Egrie JC (1990) Recombinant human erythropoietin in
anemic patients with end-stage renal disease: results of a phase
III multicenter clinical trial. Ann Int Med 111(12):992–1000
lin M (2012) Systematic review of the impact of erythropoiesis-
stimulating agents on fatigue in dialysis patients. Nephrol Dial
Transpl 27(6):2418–2425
6. McMurray J, Parfrey P, Adamson JW, Aljama P, Berns JS, Bohlius
J (2012) Kidney disease: improving global outcomes (KDIGO)
anemia work group. KDIGO clinical practice guideline for anemia
in chronic kidney disease. Kidney Int Suppl 2(4):279
7. Tanhehco YC, Berns JS (2012) Red blood cell transfusion risks in
patients with end-stage renal disease. Semin Dial 25(5):539–544

13

8. Pfeffer MA, Burdmann EA, Chen CY, Cooper ME, De Zeeuw D,
Eckardt KU (2009) A trial of darbepoetin alfa in type 2 diabetes
and chronic kidney disease. N Engl J Med 361(21):2019–2032
9. Singh AK, Szczech L, Tang KL, Barnhart H, Sapp S, Wolfson M
(2006) Correction of anemia with epoetin alfa in chronic kidney
disease. N Engl J Med 355(20):2085–2098
10. United States Renal Data System. 2018 USRDS annual data
report: Epidemiology of kidney disease in the United States.
National Institutes of Health, National Institute of Diabetes and
Digestive and Kidney Diseases, Bethesda, MD. https:​ //www.usrds​
.org/2018/view/v2_02.aspx. Accessed 17 Feb 2019
11. Goel R, Chappidi MR, Patel EU, Ness PM, Cushing MM, Frank
SM (2018) Trends in red blood cell, plasma, and platelet transfu-
sions in the United States, 1993–2014. JAMA 319(8):825–827
12. St Peter WL, Guo H, Kabadi S, Gilbertson DT, Peng Y, Pend-
ergraft T (2018) Prevalence, treatment patterns, and healthcare
resource utilization in Medicare and commercially insured non-
dialysis-dependent chronic kidney disease patients with and with-
out anemia in the United States. BMC Nephrol. 19(1):67. https​://
bmcne​phrol​.biome​dcent​ral.com/track​/pdf/10.1186/s1288​2-018-
0861-1. Accessed 19 May 2019
13. Gill KS, Muntner P, Lafayette RA, Petersen J, Fink JC, Gilbertson
DT (2013) Red blood cell transfusion uses in patients with chronic
kidney disease. Nephrol Dial Transpl 28(6):1504–1515
14. Vaziri ND, Zhou XJ (2008) Potential mechanisms of adverse out-
comes in trials of anemia correction with erythropoietin in chronic
kidney disease. Nephrol Dial Transpl 24(4):1082–1088
15. Hsu CY, McCulloch CE, Curhan GC (2002) Epidemiology of
anemia associated with chronic renal insufficiency among adults
in the United States: results from the Third National Health and
Nutrition Examination Survey. J Am Soc Nephrol 13(2):504–510
16. Moreno F, Aracil FJ, Pérez R, Valderrábano F (1996) Controlled
study on the improvement of quality of life in elderly hemodialysis
patients after correcting end-stage renal disease-related anemia
with erythropoietin. Am J Kidney Dis 27(4):548–556
17. Levin A, Singer J, Thompson CR, Ross H, Lewis M (1996)
Prevalent left ventricular hypertrophy in the predialysis popula-
tion: identifying opportunities for intervention. Am J Kidney Dis
27(3):347–354
18. Parfrey PS, Lauve M, Latremouille-Viau D, Lefebvre P (2009)
Erythropoietin therapy and left ventricular mass index in CKD
and ESRD patients: a meta-analysis. Clin J Am Soc Nephrol
4(4):755–762
19. Palmer SC, Navaneethan SD, Craig JC, Johnson DW, Tonelli
M, Garg AX (2010) Meta-analysis: erythropoiesis-stimulating
agents in patients with chronic kidney disease. Ann Intern Med
153:23–33
20. Johnson DW (2016) Erythropoietin corrects anemia and reduces
the risk of blood transfusion in people with chronic kidney dis-
ease, but has uncertain effects on other patient-level outcomes.
BMJ Evid-Based Med 21:178
21. Palmer SC, Saglimbene V, Craig JC, Navaneethan SD, Strippoli
GFM (2014) Darbepoetin for the anemia of chronic kidney dis-
ease. Cochrane Database Syst Rev (3):CD009297. https​://www.
cochr​aneli​brary​.com/cdsr/doi/10.1002/14651​858.CD009​297.
pub2/epdf/full. Accessed 19 May 2019
22. National Collaborating Centre for Chronic Conditions, Royal Col-
lege of Physicians (2015). Guideline on anaemia management
in chronic kidney disease. National Institute for Clinical Excel-
lence. Available on http://www.nice.org.uk/guida​nce/NG8/evide​
nce. Accessed 26 Aug 2019
23. Locatelli F, Bárány P, Covic A et  al (2013) Kidney disease:
improving global outcomes guidelines on anaemia management
in chronic kidney disease: a European renal best practice position
statement. Nephrol Dial Transpl 28(6):1346–1359
13
Journal of Nephrology
24. Besarab A, Bolton WK, Browne JK, Egrie JC, Nissenson AR,
Okamoto DM (1998) The effects of normal as compared with low
hematocrit values in patients with cardiac disease who are receiv-
ing hemodialysis and epoetin. N Engl J Med 339(9):584–590
25. Chaknos CM, Berns JS (2013) Erythropoiesis-stimulating agents
on trial: are higher dosages causing harm? Am J Kidney Dis
61(1):6–8
26. Carson JL, Triulzi DJ, Ness PM (2017) Indications for and adverse
effects of red-cell transfusion. N Engl J Med 377(13):1261–1272
27. Zou S, Dorsey KA, Notari EP, Foster GA, Krysztof DE, Musavi F
(2010) Prevalence, incidence, and residual risk of human immu-
nodeficiency virus and hepatitis C virus infections among United
States blood donors since the introduction of nucleic acid testing.
Transfusion 50(7):1495–1504
28. Blajchman MA, Goldman M, Freedman JJ, Sher GD (2001) Pro-
ceedings of a consensus conference: prevention of post-transfu-
sion CMV in the era of universal leukoreduction. Transfus Med
Rev 15:1–20
29. Fang DC, McCullough J (2016) Transfusion transmitted Babesia
microti. Transfus Med Rev 30:132–138
30. Scornik JC, Bromberg JS, Norman DJ, Bhanderi M, Gitlin M,
Petersen J (2013) An update on the impact of pre-transplant
transfusions and allosensitization on time to renal transplant
and on allograft survival. BMC Nephrol 14:217. https​://bmcne​
phrol​.biome​dcent​ral.com/track​/pdf/10.1186/1471-2369-14-217.
Accessed 19 May 2019
31. Opelz G, Graver B, Mickey MR, Terasaki P (1981) Lymphocy-
totoxic antibody responses to transfusions in potential kidney
transplant recipients. Transplantation 32(3):177–183
32. Naci H, de Lissovoy G, Hollenbeak C, Custer B, Hofmann A,
McClellan W et al (2012) Historical clinical and economic con-
sequences of anemia management in patients with end-stage renal
disease on dialysis using erythropoietin stimulating agents ver-
sus routine blood transfusions: a retrospective cost-effectiveness
analysis. J Med Econ 15(2):293–304
33. Glenngård AH, Persson U, Schön S (2008) Cost-effectiveness
analysis of treatment with epoetin-α for patients with anemia
due to renal failure: the case of Sweden. Scand J Urol Nephrol
42(1):66–73
34. Maoujoud O, Ahid S, Cherrah Y (2016) The cost-utility of treating
anemia with continuous erythropoietin receptor activator or Epo-
etin versus routine blood transfusions among chronic hemodialysis
patients. Int J Nephrol Renovasc Dis 9:35–43
35. Hauber B, Caloyeras J, Posner J, Brommage D, Tzivelekis S,
Pollock A (2017) Hemodialysis patients’ preferences for the
management of anemia. BMC Nephrol. 18(1):254. https​://bmcne​
phrol​.biome​dcent​ral.com/track​/pdf/10.1186/s1288​2-017-0664-9.
Accessed 19 May 2019
36. Collins AJ, Foley RN, Herzog C, Chavers B, Gilbertson D, Ishani
A (2011) US Renal Data System 2010 annual data report. Am J
Kidney Dis 57(1 suppl 1):e1–e526
37. Collins AJ, Foley RN, Herzog C, Chavers B, Gilbertson D, Herzog
C (2013) US Renal Data System 2012 annual data report. Am J
Kidney Dis 61(1 suppl 1):e1–e476
38. Department of Health and Human Services, Centers for Medicare
& Medicaid Services(2010) 42 CFR Parts 410, 413, and 414;
medicare program; end-stage renal disease prospective payment
system; final rule and proposed rule. http://www.acces​s.gpo.gov
75[155]. Accessed 19 Mar 2019
39. FDA(2011). FDA drug safety communication: modified dosing
recommendations to improve the safe use of erythropoiesis-stimu-
lating agents in chronic kidney disease. http://www.fda.gov/Drugs​
/DrugS​afety​/ucm25​9639.htm. Accessed 29 Apr 2019
40. Centers for Medicare and Medicaid Services. https​: //www.
cms.gov/Medic​are/Quali​ty-Initi​ative​s-Patie​nt-Asses​sment​-Instr​
Journal of Nephrology
ument​s/ESRDQ​IP/Downl​oads/PY_2013_Progr​am_Detai​ls.pdf.
Accessed 29 Apr 2019
41. http://www.gao.gov/produ​cts/GAO-13-190R. Accessed 18 Mar
2019
42. Collins AJ, Monda KL, Molony JT, Li S, Gilbertson DT, Brad-
bury BD (2014) Effect of facility-level hemoglobin concentra-
tion on dialysis patient risk of transfusion. Am J Kidney Dis
63(6):997–1006
43. Cappell KA, Shreay S, Cao Z, Varker HV, Paoli CJ, Gitlin M
(2014) Red blood cell (RBC) transfusion rates among US chronic
dialysis patients during changes to Medicare end-stage renal dis-
ease (ESRD) reimbursement systems and erythropoiesis stimu-
lating agent (ESA) labels. BMC Nephrol 15:116. https​://doi.
org/10.1186/1471-2369-15-116
44. Park H, Liu X, Henry L, Harman J, Ross EA (2018) Trends in
anemia care in non-dialysis-dependent chronic kidney disease
(CKD) patients in the United States (2006–2015). BMC Neph-
rol. 19(1):318. https​://bmcne​phrol​.biome​dcent​ral.com/track​/
pdf/10.1186/s1288​2-018-1119-7. Accessed 19 May 2019
45. Fuller DS, Bieber BA, Pisoni RL, Li Y, Hal Morgenstern, Akizawa
T (2016) International comparisons to assess effects of payment
and regulatory changes in the United States on Anemia Practice
in patients on hemodialysis: the dialysis outcomes and practice
patterns study. J Am Soc Nephrol 27(7):2205–2215
46. Sibbel SP, Koro CE, Brunelli SM, Cobitz AR (2015) Characteri-
zation of chronic and acute ESA hyporesponse: a retrospective
cohort study of hemodialysis patients. BMC Nephrol. 16:144.
https​://bmcne​phrol​.biome​dcent​ral.com/track​/pdf/10.1186/s1288​
2-015-0138-x. Accessed 19 May 2019
47. Bello AK, Ribic CM, Cournoyer SH, Kiaii M, LeBlanc M, Poulin-
Costello M (2018) Transfusion Management of Incident Dialysis
Patients in Canada: A Prospective Observational Study. Can J
Kidney Health Dis. 5:2054358118778564. https:​ //www.ncbi.nlm.
nih.gov/pmc/artic​les/PMC59​92794​/pdf/10.1177_20543​58118​
77856​4.pdf. Accessed 19 May 2019
48. Fox KM, Yee J, Cong Z, Brooks JM, Petersen J, Lamerato L
(2012) Transfusion burden in non-dialysis chronic kidney disease
patients with persistent anemia treated in routine clinical practice:
a retrospective observational study. BMC Nephrol. 13:5. https​
://www.ncbi.nlm.nih.gov/pmc/artic​les/PMC32​83448​/pdf/1471-
2369-13-5.pdf. Accessed 19 May 2019
49. Lawler EV, Bradbury BD, Fonda JR, Gaziano JM, Gagnon DR
(2010) Transfusion burden among patients with chronic kidney
disease and anemia. Clin J Am Soc Nephrol 25(4):667–672
50. Whitman CB, Shreay S, Gitlin M, Van Oijen MG, Spiegel BM
(2013) Clinical factors and the decision to transfuse chronic dialy-
sis patients. Clin J Am Soc Nephrol 8(11):1942–1951
51. Foley RN, Curtis BM, Parfrey PS (2008) Hemoglobin targets and
blood transfusions in hemodialysis patients without symptomatic
cardiac disease receiving erythropoietin therapy. Clin J Am Soc
Nephrol 3(6):1669–1675. https​://doi.org/10.2215/CJN.02100​508
52. Carson JL, Stanworth SJ, Roubinian N, Fergusson DA, Triulzi D,
Doree C (2016) Transfusion thresholds and other strategies for
guiding allogeneic red blood cell transfusion. Cochrane Database
of Syst Rev. Issue 10. Art. No.: CD002042. https​://www.cochr​
anelib​ rary.​ com/cdsr/doi/10.1002/146518​ 58.CD0020​ 42.pub4/epdf/
full. Accessed 19 May 2019
53. Carson JL, Terrin ML, Noveck H, Sanders DW, Chaitman BR,
Rhoads GG (2011) Liberal or restrictive transfusion in high-risk
patients after hip surgery. N Engl J Med 365(26):2453–2462
54. Atkins D, Eccles M, Flottorp S, Guyatt GH, Henry D, Hill S
(2004) Systems for grading the quality of evidence and the
strength of recommendations I: critical appraisal of existing
approaches The GRADE Working Group. BMC health services
research. 4(1):38. https​://bmche​alths​ervre​s.biome​dcent​ral.com/
track​/pdf/10.1186/1472-6963-4-38. Accessed 19 May 2019
55. Carson JL, Guyatt G, Heddle NM et al (2016) Clinical practice
guidelines from the AABB: red blood cell transfusion thresholds
and storage. JAMA 316:2025–2035
56. Vora AN, Stanislawski M, Grunwald GK, Plomondon ME, Rums-
feld JS, Maddox TM (2017) Association Between Chronic Kidney
Disease and Rates of Transfusion and Progression to End-Stage
Renal Disease in Patients Undergoing Transradial Versus Trans-
femoral Cardiac Catheterization-An Analysis from the Veterans
Affairs Clinical Assessment Reporting and Tracking (CART) Pro-
gram. J Am Heart Assoc. 6(4):e004819. https​://www.ahajo​urnal​
s.org/doi/pdf/10.1161/JAHA.116.004819​ . Accessed 19 May 2019
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