3 s2.0 B9781455748365000576 PDF

Hematologic Aspects of 57
Kidney Disease
Carlo Brugnara | Kai-Uwe Eckardt
CHAPTER OUTLINE
ANEMIA OF KIDNEY DISEASE, 1875 DISORDERS OF HEMOSTASIS IN CHRONIC

Definition and Prevalence of Anemia in KIDNEY DISEASE, 1904
Chronic Kidney Disease, 1875 Bleeding and Chronic Kidney Disease, 1904
Pathobiology of Anemia in Chronic Kidney Hypercoagulability and Chronic Kidney
Disease, 1878 Disease, 1906
Anemia of Chronic Kidney Disease, 1884 Heparin-Induced Thrombocytopenia, 1909
Association of Anemia with Adverse WHITE CELL FUNCTION IN CHRONIC KIDNEY
Outcomes, 1888 DISEASE, 1909
Erythrocytosis of Patients with Kidney Leukocyte (Monocyte) Activation, 1909
Disease, 1888 Leukocyte Functional Impairment, 1909
Treatment of Renal Anemia, 1889 Markers of Leukocyte Activation, 1910
ANEMIA OF KIDNEY DISEASE for adult women.8 This definition has been adopted in the
clinical practice guideline for anemia in CKD developed by
Reduced erythrocyte mass, or anemia, is one of the regular Kidney Disease: Improving Global Outcomes (KDIGO),9
consequences of chronic kidney disease (CKD) because of whereas previous guidelines have proposed a slightly higher
the central role played by erythropoietin (EPO) in the regu- threshold in men (13.5 g/dL).10,11 Persons living at higher
lation of erythropoiesis. Anemia can manifest itself early in altitudes are characterized by a larger red blood cell mass
the course of CKD, and its severity and prevalence go pari and reduced Hgb oxygen affinity, compensatory changes
passu with the progression of kidney disease. Given the sig- required to maintain tissue oxygen delivery in the reduced
nificant effect of severe anemia on quality of life among ambient oxygen tension at such altitudes.12-18
patients with kidney failure, anemia is considered one of the The prevalence of anemia in patients with CKD has been
most clinically significant complications of this disease. Nev- widely studied. In general, anemia is more frequent at lower
ertheless, the direct consequences of CKD-related anemia levels of kidney function, becoming almost universal in
and the degree to which anemia should be corrected in end-stage kidney disease (ESKD) (Figures 57.1 and 57.2).19,20
patients with CKD remain controversial. The prevalence reported in different studies depends on
the definition of anemia and the target population. The
DEFINITION AND PREVALENCE OF ANEMIA IN most useful analyses are those that were community based,
avoiding biases inherent in studies of clinic-based popula-
CHRONIC KIDNEY DISEASE
tions. Hsu and coworkers studied 12,055 adult ambulatory
Anemia is a state characterized by a reduced mass of red subjects from health clinics in Boston, using the Cockcroft-
blood cells (RBCs) and hemoglobin (Hgb) concentration Gault equation to estimate creatinine clearance and the
in blood, resulting in reduced oxygen-carrying capacity and Modification of Diet in Renal Disease (MDRD) formula to
delivery to the body’s tissues and organs.1-3 Because direct estimate the glomerular filtration rate (GFR) indexed to
measurements of red cell mass are cumbersome and not body surface area.21 They found that mean Hct values were
readily available, anemia is defined as a reduction below the progressively lower with creatinine clearance below 60 mL/
normal range for Hgb concentration and hematocrit (Hct); min in men and below 40 mL/min in women. Moderately
these values depend on sex, race, and age with an increased severe anemia (Hct < 33%) was present in more than 20%
prevalence of anemia in the elderly population.4-7 The defi- of patients when GFR was below 30 mL/min in women and
nition of anemia is somewhat arbitrary. The World Health below 20 mL/min in men.21 Similar results have been
Organization (WHO) defines anemia as an Hgb concentra- obtained in different populations: In Japan, a study of
tion below 13.0 g/dL for adult men and below 12.0 g/dL 54,848 subjects identified an estimated GFR (eGFR)
1875
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1876 SECTION VIII — THE CONSEQUENCES OF ADVANCED KIDNEY DISEASE
1.0 threshold of 60 mL/min per 1.73 m2 for both sexes, below

0.9 which anemia prevalence increased significantly, and a
Proportion of the population
Hemoglobin level <11 g/dL

0.8 Hemoglobin level <12 g/dL threshold of 45 mL/min for the association of anemia with
69% Hemoglobin level <13g/dL
0.7 complications.22
0.6 Hsu and coworkers conducted a second study, using the
0.5 third National Health and Nutrition Examination Survey
0.4 (NHANES III) (1988-1994) of 15,971 adults aged over 18
33% 29%
0.3 years, with measurements of serum creatinine, Hgb, and
0.2 16% iron indices. Creatinine clearance was estimated using the
12% 5%
0.1 9% 7% 5% 5%
4% Cockcroft-Gault formula.23 A statistically significant lower
0
mean Hgb was found in men and women with creatinine
15 30 60 90 120 clearances below 70 mL/min and 50 mL/min, respectively,
A Estimated GFR (mL/min/1.73 m2) than in those with creatinine clearances greater than
80 mL/min. However, a mean decrease of 1.0 g/dL was
1.0 found only for those with creatinine clearances less than
95% 30 mL/min. Astor and colleagues studied the same NHANES
0.9
Proportion of the population
0.8 82% III data as Hsu and coworkers but restricted analysis to a
0.7 71% different age range, selecting 15,419 participants 20 years
0.6 67% and older.20 Anemia according to the WHO definition was
0.5 39% present in 7.3% of all participants (see Figure 57.1). Func-
43%
0.4 38% 30%
34% tional iron deficiency and absolute iron deficiency were
31% 28%
0.3 found to be important predictors of anemia.20 Another
0.2 study on the same dataset showed that Hgb values below
15% 9%
0.1 9% 8% 6% 6% 7% 11 g/dL were present in 42.2% of subjects with eGFRs below
0 30 mL/min/1.73 m2 and in 3.5% of subjects with eGFRs
15 30 60 90 120 between 30 and 60 mL/min/1.73 m2 (MDRD formula).24
B Estimated GFR (mL/min/1.73 m2) Stauffer and Fan, using the 2007-2008 and 2009-2010
NHANES dataset, estimated that 14.0% of the U.S. adult
50 population had CKD, with anemia having a twofold greater
SCr
prevalence in CKD than in the general population (15.4%
40 vs. 7.65%).25
CKD prevalence (%)
CysC
SCr and CysC The worldwide prevalence of anemia associated with CKD
30 rose from 1990 to 2010, and CKD is currently the sixth
leading cause of anemia in women and the ninth in men
20 worldwide.26
Anemia is more common among women and non-
10 Hispanic blacks: In the latter population, the risk for anemia
was generally more than twice that in non-Hispanic whites
in one study. 23 Another study reported a 3.3-fold higher
8 10 12 14 16 18 prevalence of anemia in blacks than in whites, with CKD
C Hemoglobin (g/dL) being less common in anemic blacks than in anemic whites
Figure 57.1 Prevalence of hemoglobin (Hgb) level less than 11 g/ (22% vs. 34%), suggesting a higher prevalence of non–CKD-
dL, 12 g/dL, and 13 g/dL among men (A) and women (B) 20 years related anemia as well.27 The investigators extrapolated the
and older from the Third National Health and Nutrition Examination data to the general U.S. population and estimated that
Survey (NHANES III) (1988-1994). All values are adjusted to the age approximately 1,590,000 Americans with creatinine clear-
of 60 years. C, Predicted prevalence of chronic kidney disease (CKD) ances less than 50 mL/min are anemic, with Hgb concen-
(defined as estimated glomerular filtration rate [eGFR], 1-59 mL/ trations lower than 12 g/dL.23 A targeted community-based
min/1.73 m2) using different GFR-estimating methods in U.S. adults screening program for CKD has confirmed a threefold
age 20 years or older by hemoglobin. Estimated GFR are based higher likelihood of anemia in African Americans than in
separately on serum creatinine (SCr), serum cystatin C (CysC), and
whites, as well as a twofold higher prevalence of anemia in
combined serum creatinine and cystatin C (SCr and CysC). Preva-
this higher-risk population than in NHANES population
lence curves are truncated when the number of relevant participants
is less than 30. (A and B adapted from Astor B, Muntner P, Levin A, surveys (see Figure 57.2).28 The same study reported a lower
et al: Association of kidney function with anemia. Arch Intern Med. prevalence of anemia in smokers than in nonsmokers (see
162:1401-1408, 2002; C from Estrella MM, Astor BC, Köttgen A, et al: Figure 57.2), which has been attributed to an enhanced
Prevalence of kidney disease in anaemia differs by GFR-estimating stimulation of erythropoiesis due to relative hypoxia. It has
method: the Third National Health and Nutrition Examination Survey been advocated that the traditionally accepted eGFR thresh-
[1988-94]. Nephrol Dial Transplant 25:2542-2548, 2010.) old of 60 mL/min to define “CKD” should be modified to
higher levels in African Americans, in whom metabolic
abnormalities and anemia are more common and present
at higher eGFR values than in whites.29 In a large retrospec-
tive analysis, anemia was associated equally among African
Americans and whites with ESKD.30 However, in patients on
CHAPTER 57 — Hematologic Aspects of Kidney Disease 1877
80 30%
WHO eGFR >60
70 K/DOQI eGFR 45-59
25%
eGFR <45
Prevalence of anemia (%)
60
20%
50
Prevalence
40 15%
30
10%
20
5%
10
0 0%
Stage 1 Stage 2 Stage 3 Stage 4 Stage 5 20-59 60-69 70-79 >79
Ageband
A CKD stages C
16 100
WHO 14.3 MCV microcytic
14 90
K/DOQI MCV normocytic
Prevalence of anemia (%)
12.3 80
12 MCV macrocytic
70
10 9.8
60
8 7.8 50
7.2
6.1 40
6
30
4 3.6
2.9 20
2 10
0 0
Current Nonsmoker Current Nonsmoker Normal Mildly Stage 3a Stage 3b Stage 4 Stage 5
smoker smoker eGFR impaired
eGFR
B KEEP NHANES 99-04 D Class of CKD
Figure 57.2 A, Prevalence of anemia by stage of chronic kidney disease (CKD) in the Kidney Early Evaluation Program (KEEP). B, Prevalence
of anemia by smoking status. K/DOQI, Kidney Disease Outcomes Quality Initiative; NHANES, National Health and Nutrition Examination Survey;
WHO, World Health Organization. C, Age-specific prevalence of anemia in CKD according to estimated glomerular filtration rate (eGFR).
D, Rates of microcytic, normocytic, and macrocytic anemia for each stage of CKD. MCV, Mean corpuscular volume. (A and B from McFarlane
SI, Chen SC, Whaley-Connell AT, et al: Prevalence and associations of anemia of CKD: Kidney Early Evaluation Program [KEEP] and National Health
and Nutrition Examination Survey [NHANES] 1999-2004. Am J Kidney Dis. 51[Suppl]:S46-S55, 2008; C and D from Dmitrieva O, de Lusignan S,
Macdougall IC, et al: Association of anaemia in primary care patients with chronic kidney disease: cross sectional study of quality improvement in
chronic kidney disease [QICKD] trial data. BMC Nephrol 14:24, 2013.)
dialysis, the Hgb threshold below which higher mortality (KEEP), a community-based screening initiative for patients
rates are observed is higher in African Americans than in at high risk for kidney disease.41 Anemia was more prevalent
whites (11 g/dL vs. 10 g/dL).31 In any case, observations on among patients with diabetes and developed earlier than in
race/ethnicity cannot be interpreted in isolation but must patients without diabetes mellitus. In patients with CKD
take into consideration socioeconomic status as well as cul- stage G3 (GFR 30-59 mL/min), 22.2% of those with diabe-
tural and behavioral differences. 32 tes were anemic; in patients with CKD stage G4 (GFR
For people with eGFRs of 30 to 59 mL/min/1.73 m2, low 15-29 mL/min/1.73 m2), the prevalence was 52.4%. The
concentrations of 25-hydroxyvitamin D [25(OH)D] and difference among patients with and without diabetes was
elevations in C-reactive protein (CRP) were independently most prominent in patients with CKD stage G3, in which the
associated with Hgb concentrations below 12 g/dL.33 Other prevalence of anemia was nearly threefold greater among
studies have also reported an independent association of those with diabetes. Men with diabetes were particularly
high-sensitivity CRP results with anemia in patients with prone to anemia, more so than women.
eGFRs less than 60 mL/min/m2.34 The prevalence of anemia in persons with diabetes and
Anemia develops earlier in the course of CKD, and its normal kidney function can be as high as 32%, with aggra-
magnitude tends to be more severe, in patients with diabetes vating factors being advanced age and thiazolidinedione
mellitus than in patients without diabetes.7,35-42 El-Achkar (“glitazone”) therapy.43 Symeonidis and coworkers explored
and colleagues studied 5380 community-dwelling patients the mechanism for anemia in diabetes by studying 694
surveyed as part of the Kidney Early Evaluation Program anemic individuals, of whom 237 had diabetes.42 Serum
EPO concentrations were found to be lower in subjects with 2. The prevalence of anemia begins to increase significantly
diabetes, particularly in relation to the degree of anemia with eGFR below 60 mL/minute/1.73 m2 but anemia is
present, with a significant inverse correlation between generally not a frequent or severe complication of CKD
serum EPO and the fraction of glycosylated Hgb. Thomas until GFR is below 30 mL/min × 1.73 m2.
and associates studied the contribution of proteinuria to 3. Anemia is a more significant problem for younger
anemia among 315 Australian patients with type 1 diabe- women, older men, and African Americans.
tes.40 The prevalence of anemia was found to be higher in 4. Anemia occurs earlier in the course of disease and is
patients with macroalbuminuria than in those with microal- often more severe among patients with CKD and diabetes
buminuria or with no albuminuria (52% vs. 24% vs. 8%, mellitus.
respectively). A large study of 79,985 adults with diabetes 5. Screening for anemia (measurement of Hgb) should
mellitus showed a higher risk of anemia in black subjects generally begin at CKD stage G3.
and a lower one in Asian subjects in comparison with white
subjects.44
With aging, kidney function tends to progressively decline. PATHOBIOLOGY OF ANEMIA IN CHRONIC
The interaction of aging and loss of kidney function might KIDNEY DISEASE
be expected to raise the prevalence of anemia. In actuality,
the relation is more complex. Men with CKD tend to have NORMAL ERYTHROPOIESIS
higher prevalence of anemia with older age, but among The delivery of oxygen to peripheral tissues is a highly regu-
women with CKD, anemia is more frequent at younger lated process: A crucially important determinant is red
ages.23 It is likely that the high prevalence of iron deficiency blood cell mass, which is determined by the dynamic balance
in menstruating women accounts for this difference. If anal- between the removal of older cells from the circulation and
ysis is limited to older men and women, the association the production of newer cells by the bone marrow. Under
between older age and anemia is clearer. Ble and colleagues normal conditions, approximately 1% of the circulating
studied 1005 community-living elderly in Italy (InCHIANTI erythrocytes is replaced daily, corresponding to about 250
study).45 The prevalence of anemia was found to increase billion erythrocytes, with 2.5 to 3.0 million erythrocytes
with age in both sexes. By multivariate analysis, much of the being produced each second.52 The control of red blood
risk for anemia segregated to individuals with creatinine cell mass is based on a classic negative feedback loop medi-
clearance less than 30 mL/min, who also had lower mean ated by changes in the production of the hormone EPO.
serum EPO concentrations. Another InCHIANTI analysis EPO is mainly produced in the kidney and regulates the
showed that lower than normal total and bioavailable testos- production of erythrocytes by interaction with specific EPO
terone concentrations resulted in significantly higher risk receptors (EPO-R) on bone marrow erythroid progenitors.
for development of anemia at 3-year follow-up for both men For this mechanism, to function properly, several other
and women.46 In a study of 6200 nursing home residents cofactors, like iron, vitamin B12 and folic acid, are also
(mostly Caucasian women), prevalences of anemia and CKD required.
were 60% and 43%, respectively. 47 Age was an important
determinant of anemia in the absence of CKD, whereas this Erythropoietin
effect was lost in the presence of CKD, which became the EPO, the major regulatory hormone of erythrocyte produc-
strongest determinant of anemia.47,48 One third of the tion, is a 30.4-kDa glycoprotein. Its production in the kidney
anemias found in elderly adults (older than 65 years) may is modulated by the delivery of oxygen from the circulating
be unexplained, but significant associations are present erythrocytes. When the mass of the circulating erythrocytes
between anemia and low EPO concentrations and low lym- decreases, from decreased production, enhanced destruc-
phocyte counts.49 In this setting, RBC distribution width tion, or loss of erythrocytes, the reduction in oxygen delivery
(RDW) becomes a very powerful predictor of mortality.50 results in increased production of this hormone. The first
Hemoglobin values in patients with advanced CKD are recognition of the linkage between hypoxia and erythrocyte
frequently confounded by the use of erythropoiesis- quantity arose from astute nineteenth-century observations
stimulating agents (ESAs; see later) and iron. Although on the effects of living at higher altitude.53,54 Carnot and
there had been an increase in ESA use before initiation of Deflandre first postulated that a humoral factor (a “hemo-
dialysis and in patients on dialysis in the past, this trend has poietin”) might regulate erythropoiesis.55 They injected
reversed after publication of the results of randomized con- serum from anemic rabbits into normal animals, resulting in
trolled trials (RCTs), changes in prescribing instructions, increased reticulocyte counts, and these investigators termed
and new guidelines (see later). In fact, there has now been the circulating factor hematopoietin. However, in retro-
a steady decline in the use of ESAs before initiation of dialy- spect, their observation was probably an artifact, because the
sis (Figure 57.3). The Hgb concentration at initiation of amount of serum transferred was too low and attempts to
dialysis has been declining since 2007, and in half of patients confirm their results were unsuccessful.56
beginning hemodialysis in the United States Hgb is now Forty-four years later, Reissmann rekindled interest in the
below 10 g/dL51: field with ingenious experiments in parabiotic rats (i.e.,
Taken together, the findings of the studies discussed pre- artificial conjoined animals).57 In this model, rats were
viously led to the following conclusions regarding the preva- joined by skin and muscle, ear to tail, living for 3 months in
lence of anemia in CKD: parabiosis. When one animal breathed air with low oxygen
tension and the other breathed normal air, both animals
1. Anemia is relatively uncommon in earlier stages (stages demonstrated increased bone marrow erythropoiesis. This
G1-3) of CKD. finding provided strong evidence that a humoral factor was
% with Hgb 9
% with Hgb 9–10
% with Hgb 10–11
% with Hgb 11–12
% with Hgb 12
100
10.5
Percent receiving ESA

80 30
Percent of patients
Hemoglobin (g/dl)
60
10.0 20
40
10
9.5 Hgb: with ESA 20
Hgb: without ESA % receiving ESA
0 0
95 96 97 98 99 00 01 02 03 04 05 06 07 08 09 10 11 12 HD PD 95 96 97 98 99 00 01 02 03 04 05 06 07 08 09 10 11 12
A B All patients C
5 5
4 4
Percent of patients
3 Percent of patients 3
2 2
1 All Black 1 All Black

White Other/unknown White Other/unknown
0 0
Jan Apr Jul Oct Jan Apr Jul Oct Jan Apr Jul Oct Jan Jan Apr Jul Oct Jan Apr Jul Oct Jan Apr Jul Oct Jan
D 2010 2011 2012 2013 E 2010 2011 2012 2013
Geographic variations in the percentage of patients

with at least one transfusion event, by HSA
July: 2010 July: 2011 July: 2012
1.9 3.3 1.9 3.5 1.9 3.4

F 2.1 2.3 2.6 2.9 G 2.1 2.3 2.6 2.9 H 2.1 2.3 2.6 2.9
Figure 57.3 Anemia and treatment in end-stage kidney disease (ESKD). A, Trend in hemoglobin (Hgb) levels among incident patients with
ESKD, 1995-2012 . B, Clinical indicators: percentage distribution of achieved mean hemoglobin (Hgb) among prevalent patients on hemodialysis
(HD) and peritoneal dialysis (PD). C, Trend in the percentage of patients who received pre-ESRD erythropoiesis-stimulating agent (ESA) treat-
ment, among incident ESKD patients, 1995-2012 .D, Percentage of adult patients receiving HD with one or more claims for a red blood cell
(RBC) transfusion in a month (from Medicare claims data, by race: monthly time trend from 2010-2012). E, Percentage of patients on PD 18
years or older with one or more claims for RBC transfusion in a month (from Medicare claims data, by race: monthly time trend from 2010-
2012). F-H, Geographic variations in the percentage of patients with at least one transfusion, by Health Service Area (HSA). The ESKD bundled
Prospective Payment System (PPS) was implemented in January, 2011, and appears to have directly affected the use of erythropoietin (EPO)
and other injectable therapeutics. In 2011 (G), for example, the transfusion rate for dialysis patients was 2.9% nationwide and averaged 3.5%
in the upper quintile, which included patients residing in Texas, Louisiana, and the eastern third of the country. In 2012 (1 year after implemen-
tation of the bundle) (H), the likelihood of a transfusion event was far more widespread geographically, averaging 3.0% nationwide and 3.4%
in the upper quintile, which included the eastern two thirds of the nation as well as parts of Arizona, Nevada, and California. ESA, Erythropoiesis-
stimulating agents. (A through E from United States Renal Data System: 2014 Annual data report: an overview of the epidemiology of kidney disease
in the United States, Bethesda, MD, 2014, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; F through
H from United States Renal Data System: 2013 USRDS annual data report: atlas of chronic kidney disease and end-stage renal disease in the United
States, Bethesda, MD, 2013, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases.)
Normoxia Proteasomal destruction of HIF-α
OH Binding of hydroxylated HIF to
HIF-2α
pVHL
OH the von Hippel–Lindau protein (pVHL)
CO2
succinate
OH
HIF-2α
Oxygen-dependent hydroxylation
Oxoglutarate OH of HIF-α
OH
(prolyl-hydroxylation and
PHD 1-3 aspargylhydroxylation)
O2 FIH
HIF-2α
Hypoxia
HIF-2α
HIF-β
−14 −9.5 −6 −0.4 0.7 kb
I II III IV V HRE
Binding of the HIF dimer (HIF-α plus
Kidney Negative Liver HIF-β) to the hypoxia response
ind. reg. ind. element (HRE) of the EPO gene
element element element
Figure 57.4 Schematic presentation of hypoxia-inducible factor (HIF) signaling and the oxygen-dependent control of erythropoietin
(EPO) gene expression. HIF consists of one of two oxygen-dependent α-subunits (HIF-1α and HIF-2α) and a constitutive β-subunit. For EPO
regulation, HIF-2α is the relevant isoform. In the presence of oxygen (normoxia), HIF-α is hydroxylated at two prolyl and one asparagyl residues
through prolyl-hydroxylases (PHDs 1-3) and an asparagyl-hydroxylase (factor-inhibiting HIF [FIH]), enzymes that require oxoglutarate as a
cosubstrate. Hydroxylation of the asparagyl-residue inhibits binding of the transcriptional coactivator p300 and hydroxylation of the prolyl-
residues enables binding to the von Hippel–Lindau protein, which represents the recognition component of an E3 ubiquitin ligase. Thus,
hydroxylated HIF-α is targeted for proteasomal destruction, and hydroxylated HIF that escapes destruction is not transcriptionally active. Under
hypoxia, there is no substrate (oxygen) for the hydroxylation reactions and, thus, HIF-α is stabilized, can bind to hypoxia-responsive elements
of its target genes, and can induce or enhance their transcription. The hypoxia response element (HRE) of the EPO gene is located at 5′ of the
gene; other regulatory elements determine the tissue specificity of its expression, limiting EPO expression mainly to liver and kidneys. ind.,
Inducible; reg., regulatory.
the stimulus for erythropoiesis. In 1953, Erslev definitively cortex but appeared also throughout the renal cortex when
demonstrated the erythropoietic role of the serum factor, the anemia was particularly severe.68,69 Epo production is
now termed erythropoietin.58 He infused 100 to 200 mL of regulated by a specific hypoxia-sensing mechanisms that is
plasma from bled anemic rabbits into normal rabbit recipi- based on transcription factors stabilized by hypoxia, called
ents. Reticulocyte count increased rapidly, with a fourfold hypoxia-inducible factors (HIFs, Figure 57.4).70 This regulatory
rise in cell count within 4 days of infusion.58,59 In 1957, mechanism is not unique to EPO and is based on the
Jacobson and coworkers provided indirect evidence to capability of two separate helix-loop-helix components,
suggest that the kidneys were the primary source of EPO.60 HIF-α and HIF-β, to bind as a complex to specific hypoxia-
After demonstrating that removal of a variety of different responsive DNA elements, which regulate the transcription
organs did not affect EPO production after phlebotomy, of hypoxia-inducible genes.71 The concentrations of the
they showed that nephrectomized rats and rabbits failed to β-subunit do not respond to hypoxia.72,73 The α-subunits
increase EPO production (incorporation of iron-Fe 59 into (1α, 2α, and 3α) are produced constitutively but are rapidly
erythrocytes) after blood loss.60 Further studies by Koury degraded in the presence of oxygen by the ubiquitin-
and associates and Lacombe and associates demonstrated proteasome system.74-78 In hypoxic conditions, degradation
that the cells responsible for EPO production were peritu- of the α-subunits is inhibited, leading to rapid increases in
bular interstitial cells,61,62 which were subsequently identi- HIF-α concentrations and to the formation of the HIF tran-
fied as peritubular fibroblasts, located within the renal scription complex. For EPO regulation HIF-2 appears to be
cortex.63-65 Although the nature of these cells has still not the important HIF isoform.79-84 Renal HIF-2 is required for
been fully clarified, they have been suggested to be derived hypoxia-driven EPO production; in the absence of renal
from the neural crest66 and share characteristics of HIF-2, hepatic HIF-2 becomes the main regulator of EPO
pericytes.67 production.70,79 HIF-2α, together with HIF-β, hepatocyte
It has also been shown that with growing severity of nuclear factor-4 (HNF-4), and p300, binds to a 120–base
anemia, the number of EPO-producing peritubular cells pair (bp) enhancer located at the 3′ end of the human EPO
increases. This recruitment was found mostly in the inner polyadenylation signal.52,73,85-87 This interaction results in
rapid EPO transcription followed by translation and secre- with different numbers of sialic acid residues: Isoforms with
tion of the EPO glycoprotein.88-91 higher sialic content have a prolonged half-life in the circu-
The rapid degradation of HIF-α in the presence of oxygen lation and induce greater stimulation of erythropoiesis
depends on binding of the tumor suppressor protein von despite having a lower affinity for the EPO receptor (EPO-
Hippel–Lindau (VHL), a process that results in tagging of R).118 A hyperglycosylated recombinant EPO, called novel
the molecule for proteasomal degradation via polyubiqui- erythropoiesis-stimulating protein (NESP) or darbepoetin,
tination by ubiquitin ligase.92,93 This regulatory mechanism carries two additional N-linked carbohydrate chains with up
is based on the hydroxylation of two proline residues, which to 22 sialic acid residues; the endogenous EPO has a
are critical for the recognition of HIF-α by VHL, and an maximum of 14.119 Despite a lower (approximately fivefold)
additional hydroxylation of one asparagine residue is affinity for the EPO-R, NESP exhibits a halflife in the circu-
required for HIF binding with p300.94-98 Hydroxylation at lation approximately three times longer than that of
these three sites depends on the presence of oxygen as EPO.120,121 Gross and Lodish have developed an in vitro
molecular substrate for specific hydroxylase enzymes, model accounting for the prolonged bioactivity of NESP.118
placing these enzymes in a central role for sensing oxygen They found that NESP and EPO have similar rates of inter-
and detecting hypoxia. A mutation in the VHL protein that nalization when bound to the EPO-R, with similar degrada-
impairs the degradation of HIF-α and increases EPO pro- tion and re-secretion, but that EPO dissociates at a much
duction causes so-called Chuvash congenital polycythemia, slower rate from the EPO-R than NESP, so more EPO is
an autosomal recessive disorder endemic in the mid–Volga internalized and degraded.
River region.99 HIF-2α but not HIF-1α displays a typical iron EPO is produced primarily by the liver in the fetal period;
response element (IRE) in its 5′ untranslated region (UTR), after birth, the kidneys become the major source of produc-
which has been shown in mice to constitute an important tion.63,64,108,122-125 Clearance of circulating EPO occurs by
regulatory loop for HIF-2α messenger RNA (mRNA) trans- mechanisms that have not yet been fully elucidated. The
lation in the presence of either hypoxia or iron loading.100 liver, kidneys, and bone marrow have all been studied as
This regulatory system in conditions of reduced iron avail- possible sources of EPO elimination. A small fraction of
ability would allow iron response protein 1 (IRP1) to bind either endogenous or exogenous EPO appears to be cleared
with high affinity to IRE, inhibit mRNA translation, and by filtration into the urine.126 EPO degradation products
decrease HIF-2α synthesis and EPO production. When cel- can be found in urine, but the location and mechanisms
lular iron is abundant, IRP1 loses its RNA-binding activity responsible for this degradation are not known.113
and becomes a cytosolic aconitase, resulting in de-repression An important determinant of the fate of the circulating
of mRNA translation, which increases both HIF-2α synthesis EPO is its binding to the EPO-R on erythroid cells127; the
and EPO production. relative abundance of erythroid precursors (i.e., the size of
Purification and identification of EPO is credited to the pool of erythroid progenitors) is known to modulate
Miyake and coworkers.101 From 2550 L of urine from serum EPO concentrations.128 The EPO-R is a 55-Da trans-
patients with aplastic anemia and using multiple isolation membrane protein that belongs to the cytokine receptor
steps, they obtained a small quantity of pure glycoprotein.101 superfamily.129-134 It is present on erythroid progenitors from
Purification of human EPO led to successful cloning of the the colony-forming unit–erythroid (CFU-E) stage to late
gene, reported in 1985 by Lin and associates.102 They found basophilic erythroblasts.129 The number of receptors has
that the gene encodes a protein of 193 amino acids, includ- been estimated to be around 1000 per cell. The molecular
ing a 27–amino acid leader sequence and a terminal single signaling cascade activated upon binding of EPO to EPO-R
amino acid that are cleaved during processing, resulting in has been studied in great detail. The first event seems to be
a 165–amino acid, mature EPO molecule. When these inves- the homodimerization of the receptor, which also under-
tigators introduced the gene into Chinese hamster ovary goes a conformational change. This is followed by the gen-
cells, EPO with full biologic activity was produced.102 These eration of the intracellular signal by clathrin-mediated
findings were confirmed by an almost simultaneous report endocytosis and proteolysis of the whole ligand-receptor
by Jacobs and colleagues.103 These findings led in short complex, which ultimately determines the clearance of EPO
order to the development of techniques to produce recom- from the circulation.118,135-140
binant human EPO (rhEPO). By 1989, clinical trials of Rather than intrinsic enzymatic activity, the EPO-R signal
rhEPO had demonstrated its remarkable efficacy,104-107 transduction pathway depends on the activation of Janus
leading to regulatory approval and routine clinical use of tyrosine kinases-2 (JAK2), which are physically associated
EPO as replacement treatment. with the receptor and become phosphorylated when the
EPO itself is a member of the family of class 1 cytokines.108 conformation of the receptor is changed by the binding of
The carbohydrate moiety is important for molecular stabil- EPO.141-148 Activated JAK2 phosphorylates several of the
ity, whereas the 165–amino acid protein component is criti- eight tyrosine molecules of the cytoplasmic side of the
cal for receptor binding.109-111 There are four discrete EPO-R, exposing SH2 (src homology 2) binding sites for key
carbohydrate chains, three N-linked, and one O-linked, each signaling proteins.149,150 The result is a cascade of signal
of them having two to four branches, most of which end transduction, with activation of multiple pathways, includ-
with a negatively charged sialic acid.109,112-116 The physiologic ing Ras/MAP kinase, JNK/p38 MAP kinase, JAK/STAT, the
role of the carbohydrate chains is complex: They seem to p85 regulatory subunit of phosphoinositide 3-kinase (PI3K),
be required for the in vivo biologic activity of EPO but are and AKT.151-156 Both JAK2 and the tyrosines on the cytoplas-
not essential for in vitro receptor binding or growth stimula- mic portion of the EPO-R seem to play a role in the inter-
tion of cells in culture.117 There is considerable heterogene- nalization process:157 Familial/genetic forms of polycythemia
ity in the glycosylation of EPO, resulting in multiple isoforms due to truncations in the EPO-R with absence of key
tyrosines such as Y429 and Y431 have been shown to result erythroid progenitors and precursors, in particular the
in defective internalization of the EPO-R complex, pro- CFU-E,162 and at the same time in the activation of parallel
longed signal transduction, and increased EPO sensitivity.157 molecular pathways that eventually suppress the signaling
The EPO-R endocytic machinery is critically dependent on of the receptor via tyrosine phosphatases, which dephos-
a Cb1/p85/epsin-1 pathway, which ultimately leads to recep- phorylate and inactivate JAK2, downregulate the EPO-R on
tor downregulation.158 the cell surface, and induce negative regulators such as
The interaction of JAK2 with important intermediaries in CIS/SOCS (cytokine-inducible SH2-containing protein/
signal transduction, STATs (signal transducers and activa- suppressor of cytokine signaling).163-171
tors of transcription), has been extensively studied. After An important aspect of the overall mechanism of
phosphorylation, STAT5 becomes activated and undergoes action of EPO has been elucidated by Koury and associ-
homodimerization and may translocate to the nucleus, ates, who demonstrated that EPO does not directly
where it activates EPO-inducible genes.159 In transgenic stimulate erythroid proliferation but, rather, prevents the
mice lacking both STAT5a and STAT5b, fetal anemia devel- programmed death (apoptosis) of the erythroid progenitors
ops, with increased apoptosis of erythroid progenitors due (Figure 57.5).162,172-174 Burst-forming units–erythroid (BFU-
to decreased survival of early erythroblasts.160,161 Es), named for their capacity to generate multiclustered
The signaling induced by the binding of EPO to the colonies of cells, are the earliest cell type exclusively com-
EPO-R eventually results in an increased number of mitted to the erythrocyte line.175 It is believed that these cells
(A) Normal erythropoiesis
0.42 0.40 0.38 1.00
(B) Elevated EPO levels
0.58 0.57 0.56 1.00

(C) Decreased EPO
0.25 0.33 0.25 1.00
(D) Ineffective erythropoiesis
0.58 0.36 0.30 0.33
(E) Iron-deficient erythropoiesis HRI
0.58 0.57 0.56 1.00

EPO dependence Post EPO dependence
Figure 57.5 Model of erythropoiesis based on suppression of programmed cell death (apoptosis) by erythropoietin (EPO) and het-
erogeneity in EPO dependence among erythroid cells. A, Normal erythropoiesis with an average survival rate of 40% in each of the EPO-
dependent generations. Normal erythropoiesis produces about 250 billion new erythrocytes daily even though a minority of all potential erythroid
cells survive the EPO-dependent period. B, Elevated EPO levels as found after acute blood loss or hemolysis increase average survival rates
to 57% in each EPO-dependent generation. Daily erythrocyte production increases to three times the normal amount. C, Decreased EPO levels
as found in renal failure decrease average survival rate to 28% in each EPO-dependent generation. Daily erythrocyte production is one third
of normal. D, Ineffective erythropoiesis with high EPO levels increases rates of apoptosis caused by a pathologic process such as folate or
vitamin B12 deficiency. High EPO levels are the response to decreased erythrocyte production and expand surviving cells in the early EPO-
dependent generation, but the increased rates of apoptosis in the late EPO-dependent and post–EPO-dependent stages decrease daily
erythrocyte production to one-third normal. E, Iron-deficient erythropoiesis with elevated EPO levels, resulting in a similar increase to an average
of 57% survival as seen in B, but in the post–EPO-dependent period, when hemoglobin is synthesized, heme-regulated inhibitor (HRI) prevents
apoptosis by inhibiting protein synthesis. The inhibited protein synthesis decreases the size of the erythrocytes produced and reduces daily
erythrocyte production to three fourths of the normal numbers. (From Koury M: Red cell production and kinetics. In Simon T, Snyder EL, Solheim
BG, et al, editors: Rossi’s principles of transfusion medicine, Hoboken, NJ, 2009, Blackwell Publishing.)
are produced stochastically from pluripotent stem cells. It has become apparent that erythropoiesis does not
Only a minority of BFU-Es, 10% to 20%, are in cell cycle at happen in a vacuum and thus critically depends on the
any given time; the rest remain an inert reserve of progeni- interaction of erythroblasts with the macrophages at the
tor cells. Cells then begin to take on the characteristics of center of the erythroblastic island in the marrow. A still
CFU-Es.176 BFU-Es contain only small quantities of GATA-1, undetermined fraction of basal and EPO-stimulated eryth-
a key transcription factor for erythroid development, ropoiesis requires the contact between erythroblasts and
whereas CFU-Es have much higher concentrations.177,178 central macrophages.195,196 Macrophages play a role not only
CFU-Es begin to express some attributes of mature erythro- in the proliferation and final enucleation of erythroblasts
cytes, including blood group and Rh antigens.179,180 It is at but also possibly in supplying ferritin and iron to the eryth-
the CFU-E stage that EPO exerts its greatest influence; roblast.197 In chronic inflammatory conditions, negative
CFU-E cells express the highest surface concentration of regulation of erythropoiesis may be mediated locally by
EPO-Rs of any erythrocyte precursor.175,181,182 Without EPO macrophage-produced cytokines such as tumor necrosis
present, these cells are rapidly lost to programmed cell factor-α (TNF-α), transforming growth factor-β (TGF-β),
death.183-185 EPO is an essential survival factor for erythroid interferon-γ (INF-γ), and interleukin-6 (IL-6). Osteoblasts
progenitors from the CFU-E stage all the way to basophilic are another important component of the hematopoietic
erythroblasts. There is substantial heterogeneity in the microenvironment in bone. They are able to produce EPO,
responsiveness of erythroid progenitors to EPO within a and this local production can modulate the response to
certain tissue and differentiation stage, possibly related to systemic anemia.198
the number of EPO-Rs, their functional status, or both.186
This diversity in EPO responsiveness corresponds to the 3 The Role of Iron, Folate, and Vitamin B12
log units’ range of serum EPO concentrations that can be in Erythropoiesis
measured in human patients. Because of the continuous proliferative activity of the ery-
The quantity of EPO is traditionally expressed in units, throid tissue and the associated production of large amounts
with 1 unit representing the same erythropoietic effect in of hemoglobin, adequate nutritional supplies of folate,
animals as occurs after stimulation with 5 mmol cobalt chlo- vitamin B12, and iron are essential for proper erythropoietic
ride.108 Steady-state production of small amounts of EPO function. If any of these three components is inadequate,
maintains the serum EPO concentration at approximately 10 erythropoiesis becomes unable to meet both baseline and
to 30 U/L, enough to stimulate sufficient production of stimulated demands.
erythrocytes to replace those lost to senescence.85,108 When Inefficient erythropoiesis is a distinguishing feature of
anemia or hypoxia is present, serum EPO concentrations megaloblastic anemias, with the inability of erythroid pro-
increase rapidly to as much as 10,000 U/L.88-90 Human studies genitors to progress through the cell cycle and escape apop-
indicate a sustained increase in serum EPO concentrations tosis, owing to impaired DNA synthesis and repair. Work by
after phlebotomy, with values remaining elevated for several Koury and associates has shown that the erythroid differen-
weeks.187,188 With chronic anemia, as occurs with pure red cell tiation stage most affected by either folate or B12 deficiency
aplasia (PRCA) and aplastic anemia, serum EPO remains is the one coinciding with the end of the EPO-dependent
chronically elevated, with values as much as 1000-fold higher effects and the initiation of Hgb synthesis.199,200 The expan-
than normal in very severe aplastic anemias.189-193 sion of erythroid progenitors induced by EPO creates a
Koury and associates have incorporated these basic physi- large pool of progenitors (CFU-Es and pro-erythroblasts),
ologic concepts into a model that explains how EPO regu- which are extremely susceptible to apoptosis. The ineffi-
lates erythropoiesis in a variety of pathologic conditions (see cient erythropoiesis of megaloblastic anemias is character-
Figure 57.5).52,162,194 The EPO-dependent phase of erythro- ized by a reduced number of reticulocytes and increased
poiesis encompasses in this model three generations (from serum bilirubin and lactic dehydrogenase (LDH), and
CFU-E through early erythroblasts), with each generation accelerated iron turnover. In the case of B12 deficiency, thy-
having a certain proportion of surviving cells and the midine and purine synthesis are impaired because of
remaining cells being lost by apoptosis. Owing to their unavailability of methylenetetrahydrofolate and formyltetra-
reduced EPO responsiveness (or greater EPO dependence) hydrofolate, respectively, and the trapping of folate as
most of the cells at the CFU-E become victims of apoptosis, methyltetrahydrofolate. 201 Folate deficiency affects several
so the erythropoietic production flow in a normal subject is key coenzymes that are involved in the transfer of single
produced by a relatively small fraction of progenitors that carbon units for synthesis of pyrimidines and purines and
have escaped apoptosis. When EPO concentrations increase for amino acid metabolism.
in response to hypoxia, blood loss, or hemolysis, additional A regulated iron supply capable of matching the iron
progenitors are allowed to escape apoptosis, and resulting needs of the erythroid marrow is key for proper erythropoi-
in the generation a few days later of an increased absolute esis. Intracellular availability of iron, heme, and globin
number of reticulocytes and ultimately of RBCs. If this chains have to be perfectly matched, because excess of any
response is sufficient to compensate for the decreased of these constituents is toxic for the cell. One mg of iron
oxygen-carrying capacity of blood, EPO concentrations can be adsorbed daily from the intestine, approximately 5%
decline and so does erythropoiesis. When EPO production to 10% of the 14 mg of iron contained in the average
is impaired, such as in CKD, a much greater number of cells daily Western diet. The large majority of iron used for eryth-
become apoptotic, and EPO concentrations are insufficient ropoiesis comes from recycling of iron contained in
to maintain an adequate pool of differentiating progenitors, aged RBCs via macrophages. Each milliliter of blood con-
resulting in impaired reticulocyte production and ultimately tains on average 0.5 mg of iron. Small, long-term blood
anemia. losses result eventually in the depletion of body iron stores
and development of iron-deficient erythropoiesis and excretory and endocrine function.227 Fehr and associates
anemia. Iron deficiency suppresses HIF-2alpha synthesis studied 395 patients undergoing coronary angiography,
which in turn reduces EPO production, resulting in 84% of whom had reduced creatinine clearance values.228
decreased erythropoiesis and inappropriately low reticulo- Like Radtke and colleagues, Fehr and associates found that
cyte counts for the degree of anemia.201a,201b Heme-regulated serum EPO concentrations were higher in patients with
eIF-2α (eukaryotic initiation factor 2 eIF-2α) kinase (HRI) lower Hgb, except when creatinine clearance was below
is a key master controller of globin synthesis based on iron/ 40 mL/min.227,228
heme availability.202 In iron-sufficient states, free heme binds Why EPO production by diseased kidneys is inadequately
to HRI and inhibits the phosphorylation of eIF-2α, allowing low remains incompletely understood. Some evidence sug-
globin synthesis to proceed. In iron-deficient states, HRI gests that EPO production is reduced because of the trans-
phosphorylates eIF-2α, which in turn decreases protein syn- formation of peritubular fibroblasts into myofibroblasts.229,230
thesis and erythropoiesis, with production of microcytic On the other hand, it has been demonstrated that pharma-
erythrocytes without ineffective erythropoiesis. In macro- cologic stabilization of HIF with inhibitors of the prolyl-
phages, HRI acts as a positive modulator of cytokine and hydroxylases results in significant EPO secretion from renal
hepcidin production, thus affecting both inflammation and and extrarenal tissues even in patients undergoing dialy-
iron metabolism.203 sis.231 On the basis of these findings and other circumstantial
evidence, it appears that a disturbed oxygen-sensing mecha-
nism rather than destroyed production capacity for EPO is
ANEMIA OF CHRONIC KIDNEY DISEASE
the primary cause of renal anemia. In fact, despite the
Anemia in CKD can develop because of any of the diseases or severely diminished EPO response with advanced CKD,
deficiencies that may affect individuals without kidney disease some degree of sustained feedback remains. Radtke and
such as iron deficiency, vitamin B12204,205 or folic acid defi- colleagues found that during the 6 months prior to the start
ciency,204 and chronic blood loss.206 But the form of anemia of dialysis, as anemia worsened, serum EPO concentrations
most common in CKD is a normocytic, normochromic or increased, and that in the 6 months after the start of dialysis,
slightly hypochromic207 anemia with insufficient production the opposite occurred.227 This continued response to anemia
of erythrocytes (see Figure 57.2).208-211 The etiology is multi- in patients with advanced CKD was also demonstrated by
factorial, contributors such as relative EPO deficiency, iron Walle and coworkers, who found that serum EPO increased
deficiency, blood loss, hemolysis, chronic inflammation, after hemorrhage and declined after blood transfusion in
drugs like nonsteroidal antiinflammatory drugs (NSAIDs), patients on dialysis.232 Other workers also reported that
and other factors, which may include circulating inhibitors hypoxia can increase EPO production significantly in
of erythropoiesis.211-214 The preponderance of evidence dem- anemic patients with CKD.233,234 Consistent with such obser-
onstrates that EPO deficiency is the major cause of anemia in vations and a relevant capacity for endogenous EPO secre-
CKD.215-218 Ultimately, the greatest proof of the primacy of tion in patients with CKD, a large analysis in the United
EPO deficiency in the pathogenesis of renal anemia has been States revealed that with increasing altitude—and thus lower
the consistent success of treatment with rhEPO or its deriva- blood oxygen content for any given Hgb concentration—
tives. Other contributing causes to anemia should be consid- higher achieved Hgb was observed even though lower doses
ered if the severity of anemia is much greater than expected, of ESA were used.235
if higher than usual doses of rhEPO are needed, and in the Taken together, studies in the literature indicate that in
presence of leukopenia or thrombocytopenia. patients with CKD:
ERYTHROPOIETIN PRODUCTION AND 1. Serum EPO concentrations are generally equal to or

KIDNEY DISEASE higher than those in patients without CKD.
In normal persons, serum EPO concentrations rise in 2. Mean serum EPO concentrations increase with worsen-
response to a reduction in red cell mass, in other words, ing anemia in mild-to-moderate CKD (although to an
anemia. In patients with CKD, EPO concentrations are inap- insufficient degree).
propriately low for the degree of anemia but may still be 3. Mean serum EPO concentrations become more a func-
similar to or even higher than those in normal, nonanemic tion of GFR than of Hgb concentration when the GFR
subjects.219-223 The adequacy of EPO production in response drops below around 40 mL/min.
to anemia appears to decline in rough proportion to the 4. Even with advanced CKD, the ability to produce EPO is
degree of reduction in nephron mass.224-226 Radtke and preserved and some responsiveness to lower Hgb is
coworkers measured serum EPO in 135 patients with CKD retained.
and 59 normal subjects.227 At all stages of CKD, serum EPO
values were found to be higher than in nonanemic normal The pronounced breakdown of EPO production in
subjects, but the relation between Hgb and serum EPO response to anemia when creatinine clearance is below
depended on the severity of CKD. Among patients with 40 mL/min fits well with the observation that clinically rel-
mild-to-moderate CKD, the correlation was inverse, with evant anemia becomes common only with moderate-to-
lower Hgb concentrations being associated with higher advanced CKD (see earlier discussion and Figures 57.1 and
serum EPO concentrations. However, among patients with 57.2).20,23
creatinine clearances below 40 mL/min, mean serum EPO
concentrations were severely depressed and uncorrelated SHORTENED RED BLOOD CELL SURVIVAL
with the degree of anemia, but directly correlated with cre- Although there are several published reports on reduced
atinine clearance, indicating a parallel loss of renal RBC survival in CKD,19,209,236 it is not clear how much it
contributes to the anemia of CKD. Several abnormalities availability or absorption.257 No significant reduction in the
have been described in uremic erythrocytes, which may dose of ESAs used to manage anemia was observed for
result in their increased premature destruction. An abnor- patients undergoing frequent hemodialysis (six times per
mal externalization of phosphatidylserine (PS), a phospho- week) in comparison with those on the conventional three
lipid normally present only on the inside of the RBC times per week schedule.258
membrane, has been associated with increased erythropha-
gocytosis and anemia in CKD. 237 Uremic RBCs have been IRON METABOLISM, HEPCIDIN, AND ANEMIA OF
reported to become more fragile in response to osmotic CHRONIC DISEASE
stimuli,238 although this finding was not confirmed in pedi- Patients with CKD are in negative iron balance due to
atric patients undergoing peritoneal dialysis.239 The rheo- increased blood loss (see earlier), which frequently cannot
logic properties of uremic erythrocytes are altered owing to be adequately compensated. In the absence of chronic
changes in RBC shape and decreased deformability.240 inflammation, blood loss leads to a reduction of serum fer-
Uremic erythrocytes may not be able to mount an effective ritin and serum iron, and a progressive increase in the
response to oxidative stress,241-243 possibly because of gluta- desaturation of transferrin, below the 16% threshold that
thione deficiency,244 and may benefit from the antioxidant guarantees a normal supply of iron to the erythroid marrow.259
effects of vitamin E bound to dialysis membranes.243,245 Car- Some studies have reported reduced intestinal iron absorp-
nitine deficiency may also contribute to the reduced survival tion in patients on maintenance dialysis,260,261 mostly due to
of uremic erythrocytes.246,247 An abnormal deposition of the concomitant inflammation. However, other studies have
complement onto erythrocytes in CKD could also play a role shown it to be upregulated by EPO administration and not
in their premature removal from the circulation.248 Because substantially impaired in comparison with that in normal
the contribution to shortened RBC life span of each of these subjects.262,263 The chronic inflammatory state frequently
factors is variable from patient to patient and not easily accompanying CKD creates additional constraints to the
quantifiable, and because there are no simple, reliable proper absorption and utilization of iron.257
methods to measure RBC survival, it is extremely difficult to The identification of hepcidin as a key regulator of iron
identify anemic patients who are particularly affected, unless homeostasis in normal conditions and in ACD has redefined
they have a preexisting RBC disorder. our understanding of iron homeostasis in CKD (Figure
57.6).264-271 Hepcidin, a 25–amino acid peptide produced
BLOOD LOSS and secreted by the liver,272 modulates iron availability by
Excessive bleeding has long been recognized as a common promoting the internalization and degradation of ferropor-
and significant complication of CKD. The coagulopathy of tin,273 a key iron transporter (so far the only identified
CKD, discussed in the final section of this chapter, is thought mammalian iron exporter) that is essential for both iron
to play a major role in the occult blood loss via gastrointes- absorption in the duodenum and recycling of iron/iron
tinal bleeding of patients with CKD.249 In addition, blood efflux by macrophages.274,275 High hepcidin concentrations
loss due to the dialysis procedure and associated laboratory turn off both duodenal iron absorption and release of iron
studies is also significant. A classic paper published 30 years from macrophages; low hepcidin concentrations promote
ago estimated the blood loss due to hemodialysis to be iron absorption and heme iron recycling/iron mobilization
between 1 and 3 liters per year.250 Subsequent improvements from macrophages. Thus, hepcidin concentrations are
in dialysis techniques and clinical laboratory testing meth- expected to be high in iron overload states and diminished
odology have reduced this loss considerably. Later estimates in iron deficiency states. In normal subjects, an oral iron
of the blood lost within the whole extracorporeal circuit for load produces a measurable increase in hepcidin concentra-
each dialysis session vary from a range of 0.5 to 0.6 mL 251 tions.276 A hepcidin knockout mice model shows increased
to a median of 0.98 mL (range 0.01 to 23.9 mL).252 Each iron absorption, increased liver iron concentration, and
milliliter of blood contains approximately 0.5 mg of iron, so decreased reticuloendothelial iron stores.265 Hepcidin over-
an important consequence of blood loss is the loss of iron expression in mice leads to severe iron deficiency.277 Some
and the development of iron deficiency (see later). of the genetic forms of hemochromatosis, like juvenile
hemochromatosis, are caused by mutations in the hepcidin
UREMIC “INHIBITORS” OF ERYTHROPOIESIS gene.278 Hepcidin production can be induced by type II
Although a variety of uremic toxins have been identified in acute inflammatory reactions, which are mediated by IL-6
CKD,253,254 including some with hematologic effects such as but not IL-1 or TNF-α,279,280 thus providing a mechanism for
quinolinic acid255 and N-acetyl-seryl-aspartyl-lysyl-proline inflammation to affect iron availability and causing the
(AcSDKP),256 there is no convincing demonstration that any ACD. Anemia, EPO administration, and hypoxia increase
of them plays a significant role in the anemia of CKD. Nev- iron absorption and mobilization by decreasing hepcidin
ertheless, the response to ESAs can be improved with dialy- production, 281,282 although hepcidin is not a direct target
sis, and the EPO doses used to treat patients with anemia in gene of HIF.283 Erythroferrone (ERFE) has been identified
CKD are much greater than the amounts endogenously as the key mediator of the erythropoietic regulation of iron
produced in normal individuals, indicating reduced respon- metabolism: ERFE production rises with increased erythro-
siveness. Apart from factors associated with anemia, it is poietic activity, leading to hepcidin suppression and mobi-
likely that inhibition of erythropoiesis in CKD also occurs lization of the iron stores.284,285
through the concomitant chronic inflammatory state, which Urinary and serum concentrations of hepcidin have been
is characteristic for the anemia of chronic disease (ACD). measured with mass spectrometry.286-288 An immunoassay for
Contributing factors include decreased EPO production or serum human hepcidin has been developed, with a lower
responsiveness plus hepcidin-induced reduction in iron limit of detection of 5 ng/mL, yielding a normal range for
Iron signal
Hypoxia Inflammatory
(via HJV, HFE, TFR2)
signal signal
Erythropoetic Hepcidin
signal
Liver
Macrophage FPN
FPN
Fe2-Tf FPN
RBCs Fe loss Duodenum
Bone marrow
Figure 57.6 Hepcidin is a central regulator of systemic iron homeostasis. Serum iron concentrations are determined by the balance of
iron entry from intestinal absorption; macrophage iron recycling; and mobilization of hepatocyte stores versus iron utilization, primarily by
erythroid cells in the bone marrow. A peptide hormone secreted by the liver, hepcidin controls iron release into the plasma by downregulating
cell-surface expression of the iron export protein ferroportin (FPN) on absorptive enterocytes, macrophages, and hepatocytes. Hepcidin pro-
duction is inhibited by erythropoietic drive and hypoxia to ensure iron availability for erythropoiesis. Hepcidin production is stimulated by iron
(through human hemochromatosis protein [HFE], hemojuvelin [HJV], and transferrin receptor 2 [TFR2]) as a negative feedback loop to maintain
steady-state iron concentrations. Hepcidin production also is stimulated by inflammation, thereby sequestering iron from invading pathogens
in the setting of infection but also causing the hypoferremia of anemia of chronic disease. FE2-Tf, Transferrin-bound iron; RBC, red blood cell.
(From Babitt JL, Lin HY: Molecular mechanisms of hepcidin regulation: implications for the anemia of CKD. Am J Kidney Dis 55:726-741, 2010.)
serum hepcidin of 29 to 254 ng/mL in men and 16 to CKD have been found to be associated with elevated ferritin
288 ng/mL in women.276 The assay has enough sensitivity and/or CRP concentrations and with stage 5 CKD.276,298
to detect changes in serum hepcidin due to diurnal varia- Serum hepcidin assessment by surface-enhanced laser
tion and in response to oral iron. Measurements of prohep- desorption/ionization–time-of-flight (SELDI-TOF) mass
cidin, the precursor of the biologically active 25–amino spectrometry did not seem to offer any advantage as predic-
acid hepcidin, seem to be poorly correlated with those of tor of iron needs over the established, traditional markers
hepcidin and are unresponsive to known hepcidin regula- for adult patients on hemodialysis and maintenance ESA
tors.289 Several studies have measured hepcidin concentra- therapy.299 Serum hepcidin concentrations are reduced fol-
tions in CKD but have at times produced conflicting lowing dialysis treatment.300,301 Hepcidin concentrations also
results.290 A proper interpretation of these studies’ findings may vary in patients on hemodialysis owing to the presence
must consider the following caveats: First, in the presence of concomitant HFE mutations, the presence of which
of anemia, hepcidin concentrations are reduced in persons results in reduced hepcidin production.302 Other studies
with normal kidney function; thus, a normal hepcidin con- have reported normal concentrations of hepcidin in CKD
centration in CKD can be still inappropriately high for the but did not address the caveats mentioned previously.300,303
level of anemia. Second, hepcidin concentrations in healthy Although it has been suggested that hepcidin may improve
persons are reduced by 70% to 75% 24 hours after EPO the identification of iron deficiency in CKD prior to trans-
administration.291 plantation,304 more work is needed to define the role of
Residual kidney function, iron stores, erythropoiesis hepcidin in the assessment of iron status in CKD. In iron-
status, and inflammation all seem to be related to the hep- deficient persons without CKD, elevated hepcidin levels
cidin concentrations observed in CKD.292 Hepcidin concen- have been shown to predict nonresponsiveness to oral iron
trations were found in one study to be elevated in patients therapy.305
on dialysis but were not correlated with either IL-6 concen- Given the central role played by hepcidin in ACD, phar-
trations or responsiveness to treatment, although they macologic modulation of its production or bioavailability
decreased after initiation of EPO therapy.293 Progression or has potential as a new therapeutic modality. 306 In particular,
severity of anemia in patients with non-dialysis requiring the use of anti-hepcidin compounds may restore iron avail-
CKD (ND-CKD) seems to be associated with higher serum ability in ACD and improve the effectiveness of ESA
hepcidin concentrations.294,295 Elevated serum hepcidin has therapy.307 Strategies targeting hepcidin production, neu-
also been observed in anemic patients with combined renal tralizing hepcidin with specific peptides, or interfering with
(GFR 20-70 mL/min) and cardiac failure296 and in associa- the binding of hepcidin to ferroportin or with the hepcidin-
tion with both fatal and nonfatal cardiovascular events in induced endocytosis of ferroportin are under consider-
patients receiving maintenance hemodialysis.297 EPO ation.306 For conditions of iron overload, hepcidin mimetics
therapy leads to a reduction in serum hepcidin that corre- (mini-hepcidin) have shown effectiveness in vivo in animal
lates with the bone marrow response.296 Elevated serum hep- models,308 and stimulators of hepcidin production are also
cidin concentrations in pediatric and adult patients with under study.
Another regulator of iron homeostasis, growth differen- [MCH] from baseline) are helpful in identifying folate defi-
tiation factor 15 (GDF15), is induced by hypoxia and iron ciency states in patients on dialysis.331,332
depletion ,309 and down modulates hepcidin, thus contribut- Vitamin D deficiency is an independent predictor of
ing to iron overload in conditions with significant expan- anemia in early CKD33,333 as well as in normal subjects,334 but
sions of the bone marrow and inefficient erythropoiesis, whether vitamin D directly affects erythroid proliferation335
such as severe β-thalassemias.310 However, in patients or is just a marker remains to be demonstrated.336 Vitamin
with ACD, there seems to be no association between D supplementation (50,000 IU/month) in patients on dialy-
GDF15 and hepcidin concentrations, suggesting that this sis did not result in changes in Hgb concentrations in one
regulatory loop may not be active in the presence of study, although a possible EPO-sparing effect was reported.337
inflammation.310 Low plasma zinc (Zn) concentration has been reported
Transmembrane serine protease 6 (TMPRSS6) may act as with variable incidence in patients undergoing hemodialy-
a cell membrane sensor of iron deficiency, which in turn sis.338-340 A zinc supplementation trial showed measurable
suppresses hepcidin production and allows increased intes- improvements in Hgb concentrations.341
tinal absorption of iron.311 Mutations in TMPRSS6 have
been associated with iron-refractory iron deficiency anemia ALUMINUM OVERLOAD
(IRIDA),312 and population studies have identified a In past years, aluminium was commonly used in patients on
TMPRSS6 allele associated with lower serum iron and Hgb dialysis for its effects as a potent intestinal binder of phos-
concentrations.313-317 It is likely that iron metabolism in phate. Although calcium-containing and non–calcium-
patients with CKD may be similarly affected by genetic poly- containing phosphate binders have largely supplanted
morphism of TMPRSS6. aluminium, the effects of aluminium toxicity on hematopoi-
esis are of historical interest. Parenteral aluminium expo-
INFLAMMATION AND ANEMIA OF sure, either via dialysate contamination342 or through other
CHRONIC DISEASE routes,343 is still observed. The erythropoietic effects of
Inflammation may also impact on erythropoiesis indepen- aluminum toxicity are characterized by altered iron metabo-
dent of its effects on iron metabolism and RBC survival. lism,344 direct inhibition of erythropoiesis,345,346 and disrup-
Responsiveness to EPO declines in patients with CKD in the tion of RBC membrane function and rheology.347-349 In
presence of acute inflammation, bacterial infections, and dialyzed patients, the most notable hematologic effect
cancer.318 A chronic inflammatory state with elevated serum of aluminum overload is microcytic anemia,350,351 which
cytokine concentrations and decreased lymphocytes and improves with either the use of deionized water to reduce
CD4+ T cell counts has been described in patients on dialy- the aluminum content of the dialysate352 or chelation
sis.319 Serum CRP has been used to monitor or predict the therapy with desferrioxamine.353 EPO responsiveness is
hematologic consequences of inflammation.320 Inflamma- reduced in patients receiving dialysis who have higher
tory cytokines can induce anemia either via impaired pro- serum aluminum concentrations either at baseline or after
duction of EPO, via impaired erythropoietic response to a desferrioxamine challenge354 and can be restored with
EPO with suppression of erythroid progenitor differentia- desferrioxamine treatment.355 Improvement of anemia has
tion, and proliferation and possibly also via reduced RBC also been shown in patients with the use of chelation therapy
survival. TNF-α is known to directly inhibit erythropoiesis321 with desferrioxamine even in the absence of overt alumi-
as well as to reduce EPO production322: Antibody-mediated num toxicity.356,357 Interestingly, HIF destabilization requires
blockade of TNF-α produces an improvement of anemia in iron as a cofactor, and iron chelation with desferrioxamine
rheumatoid arthritis323 and in inflammatory bowel disease.324 can induce HIF, providing a possible alternative explanation
Cytokines such as TNF-α, IL-1, IL-8, IL-12, and INF-γ may for an improvement in anemia.
impair erythroid proliferation via multiple mechanisms,
including cytokine-induced apoptosis,325 downregulation of HORMONES, PARATHYROID HORMONE,
EPO-Rs, impaired production of other factors such as stem AND MARROW FIBROSIS
cell factor, and direct toxic effects on progenitors.326,327 It The inhibitory effects of parathyroid hormone (PTH) on
has also been proposed that inflammation may promote erythropoiesis are primarily indirect and a consequence of
the release of soluble EPO-Rs, which may inhibit EPO myelofibrosis.358 Secondary hyperparathyroidism is associ-
signaling and increase EPO resistance.328 Sotatercept, a ated with diminished responsiveness to EPO.359 Moreover,
novel therapeutic agent that targets activin A and possibly PTH levels were identified as effect modifiers of the eryth-
other receptors of the TGF-β superfamily, is currently under ropoietic response to EPO in adult CKD patients on hemo-
investigation for both prevention of vascular calcification dialysis.360 However, in pediatric patients no association was
and improvement of anemia in CKD.329 found between serum intact PTH and Hgb concentra-
tions.361 An increase in EPO levels and improvement in
FOLIC ACID, VITAMIN D, AND ZINC DEFICIENCIES anemia have been reported after parathyroidectomy.362,363
A net loss of folate is associated with dialysis, although the
deficit is typically compensated for by a normal diet and/or DRUGS
routine supplementation of water-soluble vitamins. Folate Use of renin angiotensin aldosterone system (RAAS) inhibi-
status is best assessed by measuring RBC folate, because the tors may induce or worsen anemia364 for several reasons.
plasma assay is affected by recent dietary intake and overes- Angiotensin II has direct facilitating effects on erythroid
timates the true prevalence of folate deficiency.330 Changes progenitor cells, which are inhibited by these compounds.365
in RBC parameters (increases in mean corpuscular/cell N-acetyl-seryl-lysyl-proline (AcSDKP), an endogenous inhib-
volume [MCV] and mean corpuscular/cell hemoglobin itor of erythropoiesis, accumulates in patients treated with
angiotensin-converting enzyme (ACE) inhibitors.256 Endog- odds of death in comparison with those for Hgb concentra-
enous EPO production may also be reduced through tions between 10 and 11 g/dL; several laboratory parameters
the hemodynamic effects of angiotensin II inhibition. related to iron status and nutrition as well as dose of dialysis
Because angiotensin II leads to preferential constriction were also associated with Hgb concentrations.207 There was
of efferent glomerular arterioles, it increases the ratio no association with mortality when Hgb was above 11 g/dL
of filtered sodium—the main determinant of renal oxygen in this cohort study, but other studies suggested that the
consumption—to peritubular blood flow and thus relationship among Hgb, comorbidities, and outcomes
oxygen supply, thereby presumably lowering peritubular extends into the normal range of Hgb, leading to the hypoth-
oxygen tension. RAAS inhibitors reverse these effects and esis that normalization of Hgb might be associated with best
therefore have the potential to mitigate renal hypoxia and outcomes. However, RCTs failed to confirm this suggestion
the signal for EPO production.366 It has also been postulated (see later). Therefore, although it is undisputable that
that RAAS inhibitors may promote anemia and EPO resis- anemia is a sensitive risk marker for adverse outcomes, its
tance via a reduction in testosterone serum concentrations role as a causal risk factor has not been established.
in men younger than 60 years.367 Myelosuppressive effects
of immunosuppressants may further contribute to anemia, ERYTHROCYTOSIS OF PATIENTS WITH
especially in the posttransplantation setting.368-370
KIDNEY DISEASE
ASSOCIATION OF ANEMIA WITH Although anemia is a typical complication of advanced
CKD, irrespective of its etiology, there are few circumstances
ADVERSE OUTCOMES
under which disorders of renal structure and function can
The availability of rhEPO greatly increased interest in the also result in abnormally high rates of RBC production,
role that anemia plays with respect to health-related quality that is, erythrocytosis. The pathogenesis of these disorders
of life (HRQOL) and prognosis of patients with CKD. A remains incompletely understood but they probably all
large number of observational studies have consistently result from increased production of renal EPO.
shown that even modest reductions in Hgb concentrations
are associated with adverse outcomes. This statement applies (POLY)CYSTIC KIDNEY DISEASE
to mortality in patients on dialysis10,371 and patients with The degree of anemia in patients with autosomal dominant
CKD not on dialysis372 as well as individuals in the general polycystic kidney disease (ADPKD) is usually somewhat less
population373 or with other complex chronic diseases, such severe than for other etiologies of CKD, although patients
as heart failure.374 A large study of 159,720 patients undergo- with ADPKD on dialysis usually require treatment with ESAs.
ing hemodialysis and receiving epoetin therapy showed that Occasionally patients with ADPKD may become polycythe-
the duration of anemia, rather than the Hgb concentration mic.387 Erythrocytosis may also develop in patients on hemo-
per se, was the most powerful predictor of short-term mor- dialysis with acquired renal cysts and single cysts.388,389 Serum
tality, with Hgb concentrations less than 11g/dL for 3 EPO concentrations in patients with ADPKD are, on average,
months or longer being associated with an increased risk of up to twofold greater than in patients with CKD from other
death.375,376 However, there is no agreement on how to best causes,234,390,391 and significant arteriovenous concentration
study Hgb variability effects on mortality, with various differences for EPO have been found in polycystic kidneys.392
methods having been applied to describe Hgb variability377 In the cyst walls of patients with ADPKD, interstitial cells
and with significant confounding attributable to variations have been shown to express EPO mRNA, and cysts derived
in Hgb concentrations among dialysis centers378 and the from proximal but not distal tubules contain increased con-
effects of ESA dosing and iron therapy.379 centrations of bioactive erythropoietin.392 In a later study,
A systematic review supported the notion that Hgb con- continuous activation of HIF was demonstrated in cyst walls
centrations below an a priori established reference range of patients with ADPKD and in a rat model of cystic kidney
(Hgb 9-10 g/dL in some studies and 11-12 g/dL in others) disease.393 The physiologic distinction between HIF-1α
are generally associated with increased all-cause mortality in expression in tubular cells and HIF-2α expression in peritu-
dialysis recipients. Similar findings have been reported in bular cells is maintained in the cyst walls. The genetic
pediatric patients on peritoneal dialysis.380 In patients with defects underlying ADPKD do not lead to HIF activation.
ND-CKD, the severity of anemia is also associated with the However, cyst expansion results in pericystic hypoxia, and
rate of decline in kidney function,381 consistent with the hypoxic stimulation of pericystic angiogenesis is believed to
concept that anemia may aggravate intrarenal hypoxia.382,383 play an important role in cyst progression.394,395 Therefore,
Moreover, anemia was found to be a strong risk factor for the enhanced production of EPO in cystic kidneys is prob-
the development of left ventricular hypertrophy,384,385 an ably due to local hypoxia and mediated via HIF activation.
established surrogate for mortality and cardiovascular It is possible that factors other than EPO, induced through
events. An increase in cardiac output as part of the compen- this pathway, contribute to cyst growth. Regional hypoxia
satory mechanisms that maintain oxygen delivery in anemia also appears to stimulate cyst growth, primarily via increased
has been considered as a possible reason for the link between fluid secretion into the cyst lumen.396
anemia and cardiac geometry.384
Other specific complications, such as proliferative reti- POSTTRANSPLANTATION ERYTHROCYTOSIS
nopathy in patients with diabetes, were found to be associ- Kidney transplantation is usually followed by full correc-
ated with anemia.386 In a relatively large (21,899) cohort of tion of renal anemia.374,397,398 Interestingly, a regular
dialyzed patients in the United States, Hgb concentrations increase in EPO production is not related to the presence
below 8 g/dL were associated with a twofold increase in the of the transplant but does correlate with the onset of graft
function,399 providing further evidence for the role of tumor-associated erythrocytosis is caused by renal cancer.417
excretory kidney function in EPO regulation. Some 10% to Conflicting data have been reported concerning serum
20% of patients manifest overcorrection and demonstrate EPO concentrations in patients with renal tumors, but at
erythrocytosis, usually within the first 6 months following least in some patients, raised EPO concentrations have been
transplantation.400-402 Graft failure is associated with anemia, found.418 Furthermore, overexpression of EPO mRNA has
and therefore polycythemia is more likely to occur in been demonstrated in renal tumors.419 In situ hybridization
patients with normal kidney function.374,390 revealed that accumulation of EPO mRNA occurs in epithe-
Increased plasma EPO concentrations have been reported lial tumor cells but not in interstitial cells of the tumor
in patients with posttransplantation erythrocytosis.403 Selec- stroma.419 The majority of clear cell renal carcinomas—the
tive venous catheterization studies and the response to most frequent type of renal cancer—are associated with
removal of the native kidneys suggest that the native kidneys mutations of the VHL gene that interfere with its ability to
are the main source of increased EPO production.403,404 target HIF for proteasomal degradation (see earlier).420
Although this suggestion clearly indicates that a sufficient Indeed, clear cell renal carcinomas contain high concentra-
production capacity for EPO may be preserved in diseased tions of HIF.421-424 Although stabilized HIF in renal tumors
kidneys, it is unclear how the secretion rate is enhanced appears to be functionally active in inducing HIF target
after transplantation. Improvement of the uremic state has genes, it is yet unclear why overexpression of EPO is con-
been speculated to play a role. Moreover, given that inflam- fined to about one third of these tumors.425 Although activa-
matory cytokines can inhibit erythropoietin production, the tion of HIF appears necessary for EPO gene expression in
application of immunosuppressive agents could theoreti- renal cell carcinoma, it is clearly not the only determinant.
cally enhance EPO formation. Interestingly, the prevalence The fact that erythrocytosis occurs far less frequently than
of posttransplantation erythrocytosis seems to be elevated overexpression of EPO in renal cancer is probably due to a
in combined kidney and pancreas transplantation,405 but variety of mechanisms causing anemia in patients with
whether the erythrocytosis is related to enhanced EPO for- cancer, which include inhibition of the effect of EPO and
mation or to insulin-stimulated pathways remains unclear. reduced iron availability. There is some albeit controversial
In some patients with posttransplantation polycythemia, the evidence suggesting that EPO has autocrine or paracrine
circulating EPO concentrations are normal or reduced, and tumor growth promoting effects.426,427
it may be that in these cases there is an increased sensitivity
of the erythroid progenitor cells to EPO or loss of other TREATMENT OF RENAL ANEMIA
feedback control mechanisms.
The most effective therapy of posttransplantation eryth- ERYTHROPOIESIS-STIMULATING AGENTS
rocytosis consists of agents blocking the RAAS.401,406-408 There Recombinant human erythropoietin was developed in the
is no evidence that angiotensin acts directly on EPO- 1980s with support from an orphan drug program. At that
producing cells, but there are several ways through which time it was unclear to what extent the anemia of patients
RAAS blockade may inhibit erythropoiesis (see earlier). with kidney disease could be influenced by application of
Alternative therapeutic strategies to reduce increased RBC the hormone as well as how many patients might benefit
concentrations after transplantation include the discontinu- from this kind of therapy. The initial clinical studies revealed
ation of diuretics, application of theophylline,407 and phle- an unexpected efficacy in patients receiving dialysis, with
botomies, which, however, can lead to iron deficiency. both high response rates and evidence that hemoglobin
concentrations could not just be increased to some extent
RENAL ARTERY STENOSIS but virtually be normalized.105,107 In the subsequent years,
Although renal artery stenosis reduces the oxygen supply to the use of recombinant EPO in patients on maintenance
the kidneys it is only rarely associated with erythrocytosis.409-412 dialysis became routine in most parts of the world. The
The data on EPO production in this situation are contradic- indication was subsequently extended to the much larger
tory. In experimental animals enhancement of EPO produc- group of patients with ND-CKD as well as to several other
tion after renal artery stenosis has been demonstrated by patient groups with anemia, including those whose cancer
some, but not all, investigators.413 A study performed in rats was treated with chemotherapy. Over the years, efficacy of
showed that graded reduction of renal blood flow to 10% the therapy and presumed benefits led to a gradual increase
of the control value caused a maximal threefold increase in in Hgb concentrations in virtually all patient groups that
serum EPO concentrations.414 Therefore, renal EPO pro- were treated (see Figure 57.3). Data from the U.S. Renal
duction appears rather insensitive to changes in renal blood Data System indicate a substantial increase in the use of
flow. Because the ratio of oxygen demand and delivery these agents (as well as intravenous [IV] iron and blood
determines local oxygen tension in the area of EPO- transfusion) in older (>67 years) adults with ESKD.428 Not
producing cells, it is possible that the two are equally surprisingly the expanded clinical use resulted in an extraor-
reduced after a reduction in renal blood flow, thus not dinary commercial success. Although investigators origi-
resulting in sufficient hypoxia to stimulate EPO gene expres- nally intended to copy the endogenous molecule as closely
sion. It has been argued that the indirect coupling of oxygen as possible, patent and marketing considerations together
demand to supply makes the kidney an ideal site for the with concepts for improving patient management resulted
oxygen sensing that controls RBC production.415 in the development of a number of derivatives of the EPO
molecule with altered pharmacokinetic properties and,
RENAL TUMORS later, the development of different molecules that can
Up to 5% of patients with renal carcinomas have eryth- directly or indirectly stimulate the EPO-R. Discussions about
rocytosis,416 and conversely, approximately a third of the appropriate terminology for all these compounds have
not been settled, but erythropoiesis-stimulating agents HD patients in the United States was below 10,000 units per
(ESA) is increasingly used to describe the heterogeneous week (Figure 57.7).
class of drugs that stimulate erythropoiesis through stimula- A number of additional epoetin preparations have
tion of the erythropoietin receptor. been developed all over the world. Some have distinct dif-
ferences in the production process—for example, epoetin
Epoetin delta was produced in a human cell line through increased
The term epoetin is usually applied to rhEPO preparations, transcription of the endogenous EPO gene,440 but this
produced by means of overexpression of the human EPO product is currently not being distributed. Other epoetins
gene in mammalian cell lines. Production in mammalian are so-called bio-similars, generic drugs that are designed as
cells rather than bacteria is required, because EPO is a copies of epoetin alfa or beta and are being licensed on the
highly glycosylated molecule and bacteria lack the ability to basis of a more limited clinical trial program after expira-
generate glycoproteins. Epoetin alfa and epoetin beta are tion of the patents for the originator compounds in
the two compounds first developed by two different compa- Europe.441 Additional epoetins are available in other parts
nies. Both are produced in Chinese hamster ovary (CHO) of the world but are not necessarily produced to the same
cells and show a high degree of similarity, with identical regulatory standards as the preparations marketed in the
protein backbones of 165 amino acids and one O-linked and United States and Europe and may show variable product
three N-linked glycosylation sites each, but with subtle dif- characteristics.442
ferences in their carbohydrate composition.429 Although the The importance of the formulation of epoetins was high-
amino acid sequence unequivocally determines glycosyl- lighted in 2002 with an upsurge in cases of antibody-
ation sites, the precise composition of the sugar side chains mediated PRCA in association with the SC use of epoetin
is also determined by the repertoire and activity of glycating alfa marketed outside the United States after a change to
enzymes, which may vary among cell lines and under differ- an albumin-free formulation. Patients affected by this com-
ent tissue culture conditions. Glycosylation of the EPO mol- plication develop neutralizing antibodies against both
ecule is not required for binding or activation of its rhEPO and the endogenous hormone, resulting in severe
receptor117; in fact the in vitro activity of deglycosylated anemia and transfusion dependence.443 The cause of this
erythropoietin is enhanced.430 However, in vivo deglycosyl- serious complication remains obscure, although circum-
ated EPO is inactive owing to rapid clearance from the stantial evidence suggested that rubber stoppers of prefilled
circulation, and the carbohydrate chains are thus responsi- syringes used for the albumin-free epoetin alfa formulation
ble for its pharmacokinetic properties. may have released organic compounds that acted as immu-
Early clinical trials in patients on hemodialysis used IV nologic adjuvants.444 Factors such as breach of the cold
epoetin administered thrice weekly; subsequently the intra- storage chain may also have played a role. In anti-EPO anti-
peritoneal (IP), subcutaneous (SC), and intradermal routes body cases observed so far, the subcutaneous application
of administration were also investigated.431,432 After IV route was usually a prerequisite. Although the unfortunate
administration, plasma EPO concentrations decay mono- combination of adverse factors leading to a temporary
exponentially, with an elimination half-life of approximately increase in antibody-induced PRCA was specific for one
4 to 11 hours.433 The apparent volume of distribution of product, a low baseline rate of PRCA also occurs with use
EPO is about one to two times the plasma volume, and the of epoetin beta and darbepoetin alfa (see later).
total body clearance is lower than for other protein hor-
mones, such as insulin, glucagon, and prolactin. The IP Darbepoetin Alfa
route was investigated as a potential means of administering Darbepoetin alfa is an EPO derivative with a further two
EPO to patients on peritoneal dialysis, but the bioavailability N-linked glycosylation sites, created by site-directed muta-
of intraperitoneal epoetin is disappointingly low, at 3% to genesis in order to prolong its plasma survival time (as dis-
8%. This application has therefore not been pursued.431,434,435 cussed earlier).119 Each of these glycosylation sites can carry
With SC. administration, peak serum concentrations of an additional four sialic acid residues. Thus, this molecule
about 4% to 10% of an equivalent IV dose are obtained at (called darbepoetin alfa or novel erythropoiesis-stimulating
around 12 hours, and thereafter they decay slowly such that protein [NESP]) contains five N-linked and one O-linked
concentrations greater than baseline are still present at 4 glycosylation chains, and has the capacity to carry up to 22
days.432,433 The bioavailability of SC epoetin is around 20% sialic acid residues, compared with a maximum of 14 sialic
to 25%. Nevertheless, SC application is even more efficient acid residues for original rhEPO. The additional glycosyl-
than IV application, allowing a dose reduction of approxi- ation on darbepoetin alfa results in a molecule weighing
mately 30% to maintain the same hemoglobin concentra- 37.1 kDa, compared with 30.4 kDa for epoetin. As intended,
tion.436,437 Presumably, the early peak concentrations of darbepoetin alfa has a longer half-life in vivo than rhEPO:
epoetin after IV injection are inefficient, and the more pro- 25.3 hours versus 8.5 hours after IV administration.121 The
longed elevation of hormone concentrations following SC elimination half-life after SC administration is around 48
application allows a more sustained stimulation of RBC pro- hours, which is approximately twice that previously reported
duction. Thrice-weekly administration has remained the for epoetin alfa or beta. A number of studies have examined
most popular dosage frequency for both IV and SC admin- once-weekly and every-other-week dosing.445 Darbepoetin
istration, although once-weekly,438 twice-weekly, and seven- alfa can both correct and maintain Hgb at these dosing
times-weekly (once-daily) dosing have all been used.439 With frequencies, and its side effect profile is very similar to that
IV epoetin, once-weekly administration is associated with of epoetin alfa or beta.431,446 Several “conversion” studies
much lower efficacy, and twice- or thrice-weekly dosing is suggested that an appropriate conversion factor for switch-
required. In 2012, the mean weekly dose of EPO in adult ing patients on epoein alfa or beta to darbepoetin alfa is
% with Hgb 9 % with Hgb 10–11 % with Hgb 12

% with Hgb 9–10 % with Hgb 11–12
100 100
80 80
Percent of patients
Percent of patients
60 60
40 40
20 20
0 0
1995 1997 1999 2001 2003 2005 2007 2009 2011 2013 1995 1997 1999 2001 2003 2005 2007 2009 2011 2013
A B
Mean Hgb (all pts)
Mean Hgb (ESA pts)
Mean weekly EPO dose (monthly average)
13.0 20,000
Mean weekly EPO dose (units/week)
13.0 20,000
Mean weekly EPO dose (units/week)

12.5 17,500 12.5 17,500
Hemoglobin (g/dL)
Hemoglobin (g/dL)
12.0 15,000 12.0 15,000
11.5 12,500 11.5 12,500
11.0 10,000 11.0 10,000
10.5 7500 10.5 7500
10.0 5000 10.0 5000

95 96 97 98 99 00 01 02 03 04 05 06 07 08 09 10 11 12 95 96 97 98 99 00 01 02 03 04 05 06 07 08 09 10 11 12
C Year D Year
80 80
Percent of patients receiving IV iron
Percent of patients receiving IV iron
70 70
60 60
50 50
40 40
30 30
20 20
10 10
0 0
95 96 97 98 99 00 01 02 03 04 05 06 07 08 09 10 11 12 95 96 97 98 99 00 01 02 03 04 05 06 07 08 09 10 11 12
E Year F Year
Figure 57.7 Anemia, erythropoiesis-stimulating agents (ESAs) and intravenous (IV) iron in patients undergoing hemodialysis and
peritoneal dialysis. A, Distribution of monthly hemoglobin (Hgb) (g/dL) levels in ESA-treated adult patients on hemodialysis (HD) for 90 days
or more. B, Distribution of monthly Hgb (g/dL) levels in ESA-treated adult (≥18 years of age) patients on peritoneal dialysis (PD) for 90 days or
more. C, Mean monthly Hgb level and mean weekly erythropoietin (EPO) dose (monthly average, expressed in units/week) in adult patients on
HD for 90 days or more. D, Mean monthly Hgb level and mean weekly EPO dose (monthly average, expressed in units/week) in adult patients
on PD for 90 days or more. E, Monthly percentage of adult HD patients receiving IV iron for 90 days or more. F, Monthly percentage of adult
PD patients receiving IV iron for 90 days or more. (From United States Renal Data System: 2014 annual data report: an overview of the epidemiol-
ogy of kidney disease in the United States, Bethesda, MD, 2014, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney
Diseases.)
200 units of epoetin to 1 µg of darbepoetin alfa. In contrast transcriptional activity, respectively (as discussed earlier).70
to epoetin alfa or beta, the dose requirements for darbepo- The HIF stabilizers, therefore, cause an increase in endoge-
etin alfa do not differ significantly between IV and SC nous EPO production.462 These drugs are orally active. They
administration routes. have been shown to effectively stimulate erythropoiesis in
monkeys463 and are currently being tested in phase 2 and 3
Methoxypolyethylene Glycol Epoetin Beta studies in patients with CKD.464,465 A phase 1/2 single-dose
Alternative bioengineering techniques to prolong the half- study comparing erythropoietin formation in small groups
life of EPO further resulted in the development of methoxy- of patients on dialysis with native kidneys and after bilateral
polyethylene glycol epoetin beta (also called continuous nephrectomy provided evidence that EPO production can
erythropoietin receptor activator [CERA]), which is a be stimulated in both extrarenal sites (presumably the liver)
PEGylated derivative of epoetin beta with an elimination and the diseased, nonfunctioning, fibrotic kidneys.231 These
half-life of around 130 hours when administered either IV data provide proof for the concept that a disturbance of
or SC.447-449 A methoxypolyethylene glycol polymer chain is the renal oxygen-sensing mechanism rather than a loss of
integrated through amide bonds between the N-terminal EPO-producing cells is the main cause of renal anemia.
amino group or the ε-amino group of lysine (predominantly There is much discussion about whether HIF stabilizers
lysine-52 or lysine-45), with a single succinimidyl butanoic upregulate not only EPO gene expression but also other HIF
acid linker. The molecular weight of CERA is twice that of target genes, such as those involved in iron metabolism and
epoetin (approximately 60 kDa). Phase III studies showed neoangiogenesis. Although some of these effects may facili-
that, because of the longer half-life time of CERA, less fre- tate an increase in hemoglobin concentrations, the long-
quent injections were sufficient to maintain stable hemoglo- term consequences—good or bad—of these other effects
bin concentrations. CERA given IV once every 2 weeks was have not been established. Interestingly, genetic causes of
found to be as safe and effective as epoetin given thrice impaired degradation of HIF, potentially comparable to
weekly for correcting anemia in patients on hemodialysis.450 long-term pharmacologic inhibition of HIF degradation,
A larger study also showed that CERA given at 4-week dosing have been identified as causes of rare polycythemias.99,466,467
intervals was not inferior to epoetin given thrice weekly in
terms of maintaining Hgb concentrations.451 Initiation and Maintenance of Therapy
Following commencement of regular therapy with ESAs, a
Other Erythropoiesis-Stimulating Agents significant increase in the reticulocyte count to around two
Several other ESAs have been developed or are currently in to three times baseline is usually evident at 1 week, and an
clinical development.452-454 These include EPO polymers, increase in Hgb concentration is seen by 2 to 3 weeks. The
EPO fusion proteins, EPO-mimetic molecule, and the increase is dose dependent, and most physicians aim for an
so-called HIF stabilizers, which induce endogenous EPO increment of not more than 1 g/dL/month in order to
formation. The ability of molecules, which are structurally minimize the risk of adverse effects. In the majority of
unrelated to EPO, to dimerize the EPO-R and activate the patients, ESA therapy is initiated at the outset of dialysis
intracellular signaling cascade was first described 20 years therapy, and according to the U.S. Renal Data System report,
ago.455 Peginesatide is an EPO-mimetic peptide that was sub- peak doses of ESA are being administered at month 2 after
sequently developed for treatment of anemia. Its amino acid initiation of dialysis.
sequence is completely unrelated to that of native or rhEPO The increase in Hgb concentration following ESA therapy
although it shares the same properties with EPO with respect is associated with an increase in RBC count. No significant
to EPO-R activation.456,457 The potential advantages of this changes in either leukocyte or platelet counts are usually
compound included greater ex vivo stability, allowing storage seen, although a moderate increase in the platelet count has
at room temperature; prolonged pharmacodynamic action, been documented in some studies. There is usually a marked
allowing once-monthly administration; and a simple manu- decline in the serum ferritin concentration and/or the
facturing process involving synthetic peptide chemistry. In transferrin saturation value after start of ESA therapy, unless
addition, because peginesatide is structurally unrelated to iron stores are being replenished in parallel, because large
EPO, it does not cross-react with anti-EPO antibodies, allow- quantities of iron are used up in the manufacture of new
ing effective treatment of anti–EPO antibody–mediated RBCs (see later).
PRCA.458 Two phase 3 studies demonstrated that peginesa- Radioisotopic blood volume studies confirmed that there
tide was not inferior to conventional epoetin in correcting is an increase in RBC mass after treatment with ESAs and it
anemia in CKD.459,460 However, for reasons that remain is associated with a compensatory reduction in plasma
unclear, peginesatide increased the risk of a combined car- volume so that the whole blood volume remains unchanged.
diovascular end point in patients with ND-CKD. 459 Accord- Early ferrokinetic studies indicated that epoetin therapy
ingly, it was approved in the United States for use in patients induces a twofold increase in marrow erythropoietic activity,
on dialysis only. Only slightly more than 6 months after its as evidenced by a doubling of marrow and RBC iron turn-
introduction, the drug was recalled as a result of postmarket- over.233,468 There is little or no change in mean RBC life span
ing reports of serious hypersensitivity reactions—including after epoetin therapy; thus the increased RBC mass is largely
fatal reactions in approximately 0.02% of patients—that accounted for by the production of greater numbers of
occurred within 30 minutes of the first IV dose and had not RBCs rather than any significant change in their survival.
been reported during clinical trials.461
The HIF stabilizers are competitive inhibitors of HIF IRON MANAGEMENT
prolyl-hydroxylases and asparaginyl-hydroxylase, enzymes Iron is the fourth most common element—after oxygen,
involved in the degradation of HIF and suppression of its silicon, and aluminium—in the Earth’s crust and the most
abundant transitional metal in the human body. Although iron deficiency was reported to be 90% for a ferritin cutoff
it plays an essential role in multiple biologic processes, such of 300 µg/L and 100% for 500 µg/L.477,478 Concerns about
as transport of oxygen, transfer of electrons, DNA synthesis, iron toxicity/overload have resulted in several guidelines
and heme-based enzymatic reactions, iron is also highly setting an upper limit for ferritin of 500 µg/L,9-11,476 above
susceptible to undergoing transition from the ferrous state which IV iron is not recommended. However, this recom-
(Fe2+) to the ferric (Fe3+) state and to generate reactive mendation is not evidence based.479 Additional factors that
oxygen species (ROS) via the Haber-Weiss-Fenton reaction, elevate serum ferritin are hyperthyroidism, liver disease
thus requiring the presence of multiple systems to prevent (associated with hepatitis C virus [HCV] and other condi-
or control this potentially harmful transition.469 tions), alcohol consumption, and oral contraceptives,
The metabolism of iron is geared toward conservation whereas vitamin C deficiency and hypothyroidism decrease
and recycling, with the gastrointestinal absorption of iron ferritin concentrations.480
in adults being tightly regulated to compensate for the daily
losses and keep the total iron pool in the body constant in Serum Iron, Transferrin, and Transferrin Saturation. The
the range of 35 to 45 mg per kg body weight. Of the iron biochemical markers serum iron, transferrin, and transfer-
pool, approximately two thirds is contained in the RBC pool rin saturation (TSAT) are routinely used in the diagnosis of
as Hgb, with the remaining fraction stored in macrophages iron deficiency states but have some important limitations:
and the reticuloendothelial system (RES), liver, and muscle Serum iron concentrations and TSAT values are sensitive to
(myoglobin). diurnal variations and to dietary intake, with serum iron
Multiple factors induce a negative iron balance in patients concentrations being higher early in the day, increased by
with CKD, including reduced intake/absorption, chronic greater iron intake with food or dietary supplements, and
losses due to occult and overt blood loss, and reduced bio- decreased in the presence of infection and inflammation.481
availability of iron due to the chronic inflammatory state Some of the biochemical methods used to measure iron are
and increased hepcidin production (see earlier). Iron losses sensitive to hemolysis and produce falsely elevated iron
in patients with CKD can be up to 5 to 6 mg iron daily (1 mg values,482 whereas other serum iron assays have been shown
iron daily in normal subjects) and cannot be adequately to perform poorly in patients on dialysis.483 Serum transfer-
compensated with oral iron supplements, because gastroin- rin can be elevated by the use of oral contraceptives and
testinal absorption is limited by the chronic inflammatory reduced with inflammation or infection. Several studies
state and hepcidin. In addition, in patients with CKD treated have shown that these traditional biochemical iron param-
with ESAs, insufficient amounts of iron are released from eters perform poorly in CKD and are inferior to some of
the body stores to meet the greater demand of ESA-driven the newer hematologic parameters described later.484-487
erythropoiesis.470 Similar evidence was provided for normal However, a lower serum iron concentration has been shown
subjects when erythropoiesis was increased by an intensive to be an independent predictor of mortality and hospitaliza-
blood donation schedule and EPO, or EPO alone, despite tion in dialysis recipients,488 and a higher TSAT value has
concomitant oral iron supplementation.471-473 been associated with lower mortality.489 A TSAT of 20% is
generally considered a threshold value below which iron
Markers of Iron Status therapy is indicated.10,11 In one study using data from the
When hematologic signs of iron-deficient erythropoiesis— National Health and Nutritional Examination Survey
reduced Hgb with abnormally low MCV and MCH, inade- (NHANES), more than 50% of the non-institutionalized
quate reticulocyte response, and low reticulocyte Hgb adult U.S. population were found to have values below
content—are associated with biochemical markers of low the “CKD thresholds” for ferritin (100 ng/mL) and TSAT
iron stores (abnormally low serum ferritin), the diagnosis (20%).490 Overall, women were far more likely to have
of absolute iron deficiency is straightforward. However, laboratory-based evidence of iron deficiency. Men with CKD
straightforward determination of iron deficiency is the had higher prevalence of iron deficiency than men without
exception rather than the rule in patients with CKD, in CKD, whereas the prevalences in women with and without
whom iron may be present in storage form but not readily CKD were similar (Figure 57.8). Serum transferrin and total
available for erythropoiesis and serum ferritin concentra- iron-binding capacity (TIBC) are dual markers of iron status
tions are increased owing to the concomitant inflammatory as well as of nutritional status and protein balance: Lower
state. Thus, the diagnosis of iron deficiency in CKD must baseline TIBC value or its decrease over time in dialyzed
rely on a variety of markers both biochemical and hemato- patients is associated with higher mortality and with the
logic and, in the most challenging cases, on the erythroid presence of protein-energy wasting and inflammation.491
response to IV iron (see later for the significant limitations
of bone marrow biopsy). These markers are determined in Serum Transferrin Receptor. Serum transferrin receptor
individual patients over time: markers with high biologic/ (sTfR) concentration is a marker of iron status that has
analytical variability, such as transferrin saturation and fer- shown promise in the evaluation of iron deficiency in
ritin, are less suitable to assess iron status than markers with patients with CKD. Transferrin receptors are shed from the
low variability, such as Hgb, Hct, and reticulocyte Hgb membrane of maturing erythroblasts and reticulocytes,
content. 474,475 either in soluble form or as vesicles.492-494 Concentration of
sTfR is abnormally elevated in iron deficiency states and has
Serum Ferritin. Serum ferritin values higher than 200 µg/L been shown to be a valuable parameter in several different
are recommended for patients on dialysis,10,11 and values of clinical conditions, including ACD.495-499 Although sTfR con-
100 µg/L should be considered the lower limit of normal centration is not affected by inflammation, it is an expres-
for patients with ND-CKD.476 The sensitivity for ruling out sion of the size of the pool of maturing erythroblasts; also,
450 independently of iron status, this parameter increases in

400 Men hyperproliferative anemias and with the use of ESAs.
Mean serum ferritin (ng/mL)
Women The STfR assay is not yet widely available, and a single
350
reference standard has been established only recently,500
300 with different methods still reporting different units and
250 normal ranges. A study in patients on dialysis with anemia
200 showed that sTfR concentrations lower than 6 mg/L (which
rule out iron deficiency; normal value 3.8-8.5) were associ-
150
ated with responsiveness to initiation of EPO therapy.501
100 However, because increased erythropoiesis by itself raises
50 the sTfR concentration, sTfR measurement could not reli-
0 ably detect functional iron deficiency in patients on main-
0–14.99 15–29.99 30–59.99 60–90 >90 tenance EPO therapy. Other studies have failed to show a
predictive value for sTfR in CKD anemia management. 502,503
A Creatinine clearance (mL/min)
A decline in sTfR concentration may reflect increases in
iron availability when IV ascorbic acid is used to mobilize
45 iron stores.504 Race-ethnicity, smoking, alcohol consump-
Mean transferrin saturation (%)
40 Men tion, and body mass index have been shown to be associated
Women with sTfR values.505,506 One can correct the sTfR for the value
35
of iron stores by also accounting for serum ferritin: The
30
sTfR/ferritin ratio provides an accurate assessment of iron
25 status and of the need for iron supplementation.493,507,508
20 However, to date, there is limited evidence to support the
15 clinical use of this or similar ratios in patients on dialysis.509-511
10
Erythrocyte Ferritin Concentration. Some studies in the
5 1990s had suggested a potential value for using erythrocyte
0 ferritin concentration as a marker of iron status in patients
0–14.99 15–29.99 30–59.99 60–90 >90 on dialysis.478,512-514 Although this assay can be run on auto-
B Creatinine clearance (mL/min) mated analyzers using the regular serum ferritin methodol-
ogy,515 the method is cumbersome, requires complete
removal of white blood cells to avoid measuring leukocyte
70
Percentage defined as iron deficient
ferritin,516 is insensitive to dynamic changes in iron status,

60 and is rarely available to clinicians.
50 Erythrocyte Zinc Protoporphyrin Concentration. The deter-
40 mination of erythrocyte zinc protoporphyrin (ZPP) concen-
trations had shown some promise to identify patients on
30 maintenance dialysis who require iron replacement
therapy.517-520 This marker is elevated in the presence of iron-
20
deficient erythropoiesis, with Zn replacing iron in the heme
10 precursor protoporphyrin.521 Erythrocyte ZPP concentration
is also elevated in the presence of lead poisoning. However,
0 the diagnostic value of erythrocyte ZPP concentration
SF 20/ SF 40/ SF 60/ SF 80/ SF 100/ appears to be inferior to that of RBC or reticulocyte param-
C TSAT 12 TSAT 14 TSAT 16 TSAT 18 TSAT 20
eters.485,522 In addition, because whole blood ZPP concentra-
Figure 57.8 Mean (A) serum ferritin and (B) transferrin saturation tion is falsely elevated in patients undergoing dialysis and in
(TSAT) as a function of creatinine clearance (CrCl) for the combined the presence of bilirubin and various drugs, careful washing
National Health and Nutrition Examination Survey (NHANES) cohorts of the RBCs is required to remove these interferences, ren-
(error bars are standard deviation [SD]). The trend for both TSAT and
dering this assay not suitable for routine clinical care.523,524
ferritin is not significant (NS) for men, but for women, P < .0001 for
serum ferritin and P < .02 for TSAT. National Kidney Foundation (NKF)
chronic kidney disease (CKD) stages relative to CrCl (mL/min) are Percentage of Hypochromic Red Blood Cells. A distin-
stage 5, 0 to 14.99; stage 4, 15 to 29.99; and stage 3, 30 to 59.99. guishing characteristic of iron-deficient erythropoiesis is the
Patients with CrCl 60 to 90 mL/min and patients with CrCl > 90 mL/min production of hypochromic, microcytic erythrocytes. Iron-
may have CKD stage 1 or 2, respectively, if other renal abnormalities deficient erythropoiesis results in an increase in the percent-
are present. C, Percentage of individuals defined as iron deficient with age of hypochromic erythrocytes (%HYPO), defined as the
the use of different threshold combinations of serum ferritin (SF) and percentage of erythrocytes with mean corpuscular hemoglo-
TSAT. The NKF Kidney Disease Outcomes Quality Initiatives (KDOQI) bin concentration (MCHC) lower than 28 g/dL, for hema-
thresholds of serum ferritin 100 ng/mL and TSAT 20% are different tology analyzers produced by Siemens Medical Solutions.525,526
from indices of iron deficiency in the non-CKD population, in which
Similar parameters (low hemoglobin density [LHD%] and
lower thresholds are generally used. The green bars indicate AND
logic, both test results below the specified threshold, and the yellow
DF-Hypo XE, respectively) are available in Beckman-Coulter
bars indicate OR logic, with either test result being below the threshold. and Sysmex instruments, respectively.527,528 A classic study by
(From Fishbane S, Pollack S, Feldman HI, et al: Iron indices in chronic
kidney disease in the National Health and Nutritional Examination Survey
1988-2004. Clin J Am Soc Nephrol 4:57-61, 2009.)
Macdougall and colleagues showed that functional iron iron and rhEPO in dialysis recipients. Fishbane and col-
deficiency induced by epoetin treatment and the response leagues randomly assigned 157 patients to two different IV
to IV iron could be detected by changes in %HYPO.470 iron management strategies: one based on CHr, in which IV
Several studies have confirmed that an increased %HYPO iron was started if CHr fell below 29 pg/cell, and one in
is a sensitive and early indicator of iron deficiency.485,529-533 A which IV iron was started if the serum ferritin concentration
European study found %HYPO to be the only independent fell below 100 ng/mL or the TSAT value below 20%.486 A
predictor of mortality among various iron status parameters, significant reduction in exposure to IV iron was obtained
with a twofold higher mortality risk for values higher than in the CHr-based management, with no differences in
10% than for values lower than 5%.534 According to the weekly EPO dosing between the two groups.486 Tessitore and
European Best Practice Guidelines for the Management of coworkers485 compared the diagnostic precision of a variety
Anaemia in Patients with Chronic Renal Failure, patients of hematologic and biochemical markers to identify subjects
with %HYPO values higher than 6% are most likely to show who exhibit an increase in Hgb in response to IV iron. A
response to IV iron therapy.476 A clinical study tested the combination of %HYPO higher than 6% and CHr less than
previous European Best Practice Guidelines for anemia 29 pg/cell showed the best diagnostic efficiency for iron
management, which recommended a %HYPO target of less deficiency (80%) based on the Hgb response to IV iron.
than 10%, by prospectively raising the delivered dose of IV Other studies have provided additional confirmation of the
iron to 228 patients to achieve a %HYPO value lower than diagnostic value of CHr,544,545 although one has questioned
2.5% and a serum ferritin concentration of 200 to 500 ng/ its superiority to TSAT,546 and only one study showed that
mL.533 In this study, the median %HYPO value decreased use of IV iron in patients with low CHr resulted in decreased
from 8% to 4%, median serum ferritin concentration weekly usage of rhEPO.547
increased from 188 to 480 ng/mL, and median rhEPO dose Several studies have also validated reticulocyte Hgb mea-
decreased from 136 to 72 IU/kg/wk, showing that a strategy surements (RET-He and Ret-Hb) generated by analyzers
aimed at achieving %HYPO values much lower than 10% produced by Sysmex.474,528,548-550 The current availability of
could be cost-effective, but it also resulted in serum ferritin the reticulocyte Hgb parameter on several analytical plat-
values in some patients much higher than those recom- forms may allow a wider utilization of this parameter.
mended by guidelines. However, reticulocyte Hgb cannot be used to assess iron
Contrary to the European studies, North American availability in the presence of either thalassemia traits (alpha
studies have failed to show value for %HYPO in assessing or beta) or megaloblastic erythropoiesis.
iron availability in dialysis recipients.535,536 The reasons for
this discrepancy are not clear. It is worth noting that %HYPO Bone Marrow Iron. Although iron staining of a bone
progressively increases with storage of the blood sample, marrow biopsy is regarded as the gold standard method of
owing to the concomitant increase in MCV and reduction assessing iron stores, widely divergent estimates of the preva-
in MCHC, and is therefore best measured within 4 hours. lence of iron deficiency have been generated by this inva-
In addition, %HYPO increases with reticulocytosis, because sive, potentially painful procedure.551-554 A study in 100
reticulocytes have lower MCHCs than mature RBCs.537 patients with ND-CKD showed that evaluation of iron stores
by iron staining of a bone marrow sternal aspirate was no
Reticulocyte Hemoglobin Content. After being released better than either TSAT or ferritin in correctly identifying
from the marrow, reticulocytes spend 18 to 36 hours in the “responders” to IV iron therapy.555 Some patients with CKD
circulation before becoming mature erythrocytes. Studies of have been found to have no stainable iron evident on sternal
the cellular characteristics of reticulocytes thus provide a bone marrow biopsy, despite the presence of normal to
real-time assessment of the functional state of the bone elevated serum ferritin concentrations.554,556 Bone marrow
marrow. Automated analyzers can determine with great pre- studies also have no value in identifying patients at risk for
cision not only the absolute number of reticulocytes but also development of functional iron deficiency with EPO therapy.
their size and Hgb concentration and content.538,539 The
reticulocyte Hgb content (CHr or RetHe), expressed in pg/ Liver Magnetic Resonance Imaging. Hepatic magnetic reso-
cell, has been extensively studied, especially in patients nance imaging (MRI) provides a noninvasive tool to esti-
treated with rhEPO.540,541 A reduction in CHr is the most mate liver iron deposition and is regarded as the gold
sensitive indicator of functional iron deficiency: Healthy standard methodology for monitoring patients with iron
subjects with normal iron stores who were treated with overload disorders. However, the number of studies apply-
rhEPO produced a substantial fraction of hypochromic, ing this technology in CKD is still very limited.557-559 In the
low–Hgb content reticulocytes when their baseline serum largest of these studies, conducted in 119 patients undergo-
ferritin levels were below 100 µg/L.472 When IV iron was ing hemodialysis and receiving IV iron in a single center
used in conjunction with EPO in normal subjects, the pro- according to current guidelines, 84% had evidence of
duction of hypochromic reticulocytes was abolished.542 hepatic iron deposition and 30% had hepatic MRI findings
Several small studies have described the value of CHr in consistent with severe iron overload.559 These data raise con-
identifying iron deficiency in dialysis recipients, mostly cerns that the use of IV iron and current thresholds for
based on the subsequent response to IV iron.487,535,536,543 A laboratory parameters may be too liberal, especially consid-
sensitivity of 100% and specificity of about 70% to 80% were ering the increased use of IV iron in the United States since
reported in one study,536 although other studies reported 2011 (see Figure 57.7). On the other hand, it has not yet
lower values.487,543 been demonstrated that the observed increases in hepatic
These initial studies led to additional large clinical trials iron are of any functional significance and/or associated
that tested the values of CHr in managing the dosing of IV with clinically relevant adverse outcomes.
Iron Balance Considerations. As already mentioned, of free iron, which has vasoactive effects and can produce
1 mL of blood normally contains 0.5 mg of iron and pro- hypotensive and/or anaphylactoid reactions. This risk
portionately less when the Hgb concentration is reduced. involves mainly semilabile iron-sugar complexes like iron
An estimated annual blood loss of 2 L in a dialysis recipient sucrose and iron gluconate, and not more stable complexes
with moderate anemia (20% reduction in Hgb) therefore like ferric carboxymaltose, ferumoxytol, and iron dextran.
roughly corresponds to 0.8 g of iron loss. Irrespective of all Several preparations of IV iron are meanwhile available
parameters of iron metabolism, IV iron supplementation in in the United States and European market (Table 57.1):
excess of this amount results in positive iron balance unless
blood loss (and thereby iron loss) is more pronounced than Lower-molecular-weight iron dextran, produced by PharmaCos-
anticipated. When patients were categorized according to mos, Holbaek, Denmark, is in use both in the United
their level of hepatic iron deposition, the average monthly States (INFeD, Actavis, Dublin) and Europe (Cosmofer,
iron dose was 150 mg and 283 mg in those with signs of mild Pharmacosmos, Holbaek, Denmark; Ferrisat, H.A.C.
and moderate iron overload, respectively, compared with Pharma, Caen, France); it has a significantly better toler-
100 mg in those without.559 ability and fewer side effects than the higher-molecular-
weight product, which has now been removed from U.S.
Intravenous Iron Therapy and European markets.567-573
There is general agreement that oral iron therapy is insuffi- Iron sucrose (Venofer, produced by Vifor, St. Gallen, Switzer-
cient to properly support the functional needs of EPO- land, and marketed in the United States by American
stimulated erythropoiesis in patients with ESKD. A systematic Regent Laboratories, Inc., Shirley, NY) is used worldwide
review and meta-analysis have shown that the Hgb response in the treatment of renal anemia and is the most used
is much more potent with IV iron than with oral iron, with parenteral iron preparation in the United States.574 Aller-
this effect being more substantial in patients on dialysis gic reactions have been reported in less than 1/100,000
and of a lower magnitude in patients with ND-CKD.560,561 infusions. IV injection into rats of three different com-
Similar data were obtained in a systematic Cochrane mercial preparations of iron sucrose resulted in different
analysis, which identified significant associations of IV iron degrees of inflammation and oxidative stress, suggesting
therapy with increased Hgb, ferritin, and transferrin satura- that the stability of the iron complex may differ from one
tion values as well as reduced ESA requirements, with no iron sucrose preparation to another.575
differences in mortality.562 Cost-effectiveness of IV iron Ferric gluconate (Ferrlecit, marketed in the United States by
therapy has also been demonstrated under the assumption Sanofi Aventis US, Bridgewater, NJ) is the second most
that a higher mortality risk is associated with Hgb levels less commonly prescribed IV iron preparation in the United
than 9.0 g/dL.563 States and is frequently used worldwide in patients on
Nevertheless, oral iron may be effective in patients with hemodialysis.576
ND-CKD. The FIND CKD (Ferinject assessment in patients Ferric carboxymaltose (Ferinject, Vifor; Injectafer, American
with iron deficiency anemia and Non-Dialysis-dependent Regent Inc., Luitpold Pharmaceuticals, Shirley, NY) is the
Chronic Kidney Disease) study compared the efficacy and newest iron preparation registered in both Europe and
safety of oral iron with IV administration of ferric carboxy- the United States. 577 A significant advantage of this prepa-
maltose targeting two different serum ferritin ranges, 100 ration is the possibility of infusing up to 750 mg of iron
to 200 µg/L and 400 to 600 µg/L.564 Although the IV therapy in a short time (15 min) with minimal side effects.578,579
targeting the higher ferritin range showed greater efficacy, Transient hypophosphatemia has been reported in
there was no difference in Hgb concentration or the need patients without CKD and in those with ND-CKD treated
to switch to other anemia therapy between the IV arm tar- with ferric carboxymaltose, possibly mediated by a
geting the lower ferritin range and the oral iron therapy decreased tubular reabsorption of phosphate.580,581
arm.565 Ferric citrate (Zerenex, Keryx Biopharmaceuticals, Ferumoxytol (Feraheme, AMAG Pharmaceuticals, Inc., Lex-
New York, NY) a newly developed iron-containing phos- ington, MA) is an iron oxide nanoparticle with polyglu-
phate binder, was shown to reduce serum phosphate and cose sorbitol carboxymethylether coating designed to
increase TSAT values and to moderately increase Hgb levels minimize immunologic sensitivity and release of free
in comparison with placebo in patients with ND-CKD, pro- iron, allowing a rapid injection (17 to 60 sec, currently
viding support for the potential use of this product as an approved infusion time >15 min) of a large dose (510 mg)
oral iron supplement in this patient group.566 However, the of iron, which can be repeated after 3 to 8 days.582-585
U.S. Food and Drug Administration (FDA) has approved Efficacy and adverse events in patients with CKD were
the product only as a phosphate binder and placed a safety found to be similar to those of iron sucrose.586 Ferumoxy-
warning for a potentially excessive elevation of iron stores. tol is the only IV iron preparation possessing super mag-
Several IV iron preparations are available for clinical use, netic properties, similar to MRI contrast agents, which
most of them containing iron associated with a carbohy- may alter MRI findings for up to 3 months owing to its
drate shell. The strength or lability of this association is uptake into the reticuloendothelial system.583 On the
crucial for dosing, with the most stable preparations, like basis of the studies used for FDA registration, 0.2% of
iron dextran, being suitable for large dose replacements, treated subjects experienced anaphylaxis or anaphylac-
and the more labile preparations, like iron gluconate, toid reactions, and 3.7% had hypersensitivity-type reac-
requiring multiple dosing with a single-dose maximum of tions (pruritus, rash, urticaria, or wheezing); 1.9% of
approximately 100 mg. Intravenous iron infusion may lead patients had hypotension, and 3 patients experienced
to some immediate binding of the infused iron to transfer- serious hypotensive reactions.583 The development of
rin, resulting in its complete saturation and the generation nephrogenic systemic fibrosis following gadolinium use

Table 57.1 Intravenous Iron Preparations
FDA Approved Not FDA Approved

Na Ferric Ferric
Generic Name Iron Dextran Iron Sucrose Gluconate Carboxymaltose Ferumoxytol Iron Isomaltoside 1000
Trade Name USA INFed (Actavis) Venofer (American Ferrlecit (Sanofi/ Injectafer (Luitpold/ Feraheme (AMAG Monofer (Pharmacosmos
(marketed by) Regent Inc., Luitpold Aventis), Nulecit American Regent, Pharmaceuticals, Inc.) A/S)
Pharmaceuticals, Inc.) (Actavis) Inc.)
Trade Name(s) Europe Cosmofer, Uniferon, Venofer, Idafer, Ferrlecit, Ferlixit Injectafer, Ferinject Rienso Monofer, Monover,
Ferrisat FerroLogic, Ferion, Monoferro, Diafer
Venotrix, Fermed,
Netro-Fer
Carbohydrate Dextran polysaccharide Sucrose Gluconate Carboxymaltoside Polyglucose sorbitol Isomaltoside
(LMW) carboxymethylether
Molecular weight (kDa) 165 34-60 289-444 150 750 150
Iron, mg/mL 50 20 12.5 50 30 50 or 100
Hemodialysis, mg/ 100 100 125 — 510 100-200 (UK)
session
Peritoneal dialysis 100 1 × 300 mg — 510
1 × 300 mg after 14 d
1 × 400 mg after 14 d
CKD, nondialysis 100 200 mg or 500 mg 750 mg 510
TDI possible? Yes No No Yes No Yes
Maximum approved 100 mg 400 125 mg 750 mg for body 510 mg Up to 20 mg/kg (UK)
dose weight > 50 kg
Maximum safe dose TDI over 1-4 hr 400 mg over 2 hr 250 mg over 1 hr 750 mg over 510 mg in > 15 min 20 mg/kg over 15 min
15 min
Premedication? No No No No No No
Test dose required? Yes No No No No No
“Black Box” warning Yes No No No Yes NA
(FDA)?
Adverse reaction(s) Hypophosphatemia Alteration of magnetic
resonance imaging
findings
Preservative None None Benzyl alcohol None None None
CKD, Chronic kidney disease; FDA, U.S. Food and Drug Administration; NA, not applicable; TDI, tolerable daily intake.
FDA warnings: Iron dextran and Ferumoxytol, fatal allergic reactions.
CHAPTER 57 — Hematologic Aspects of Kidney Disease
1897
has prompted the use of ferumoxytol as an alternative powered studies comparing adverse events rates between
MRI contrast agent in patients with CKD stage 4 or 5, and lower-molecular-weight iron dextran and iron sucrose.595
in dialysis-dependent CKD.587,588 The amount of labile iron, which differs among the various
Ferric isomaltoside (Monofer, Pharmacosmos A/S) is based on IV iron preparations, is likely an important determinant of
a nonbranched carbohydrate, which does not form the possible oxidative and nitrosative stress.596
typical spheroidal iron carbohydrate nanoparticle like
other IV iron preparations and seems to be associated Infection Risk and Intravenous Iron Therapy. In vitro data
with lower immunogenic potential. Monofer can be seem to support the notion that iron can promote bacterial
administered in a single dose, with dosages up to 20 mg/ growth and at the same time impair leukocyte func-
kg. Monofer is currently approved and marketed in 28 tion.522,597-600 IV injection of iron sucrose in dialyzed patients
countries, including 21 European Union members, but has been associated with the dose-dependent appearance of
not in the United States. markers of oxidant damage in lymphocytes and a decrease
in plasma ascorbate and alpha tocopherol in some studies601
A study on IV iron use for the period 1994 through but not in others.602-604 In addition, studies have not
2002 in the United States indicated that iron sucrose and accounted for the fact that the capability of leukocytes to
ferric gluconate were the predominant forms of IV iron cope with oxidant damage is markedly affected by polymor-
used in CKD, with 84.4% of hemodialysis and 19.3 of peri- phisms in glutathione S-transferase M1.605 Although there is
toneal dialysis patients having some form of IV iron indirect and inconclusive evidence for an association
therapy.589 between iron stores and bacteremia,597 most studies have
Parenteral iron administration has increased substantially failed to show an association of IV iron therapy with an
in the United States, most likely because of a shift in reim- increased risk of infection in dialyzed patients.522,599-600 Many
bursement practices toward a bundled/capitated model studies attempting to link iron status and risk of bacterial
(see Figure 57.7). Data from the Dialysis Outcomes infection have used serum ferritin, an unreliable marker of
and Practice Patterns Study (DOPPS) show IV iron use iron status in CKD, as discussed previously.597,606-610 One
increasing from 55% to 66% to 68% of patients on hemo- study showed that in patients receiving more than 10 vials
dialysis between 2010 and 2012.590 Similar trends have been of 100 mg iron dextran over 6 months, there was an
reported for European countries, Japan, Australia, and New increased risk of death and hospitalization.611 One uncon-
Zealand.591 A ferritin threshold of 800 ng/mL is now com- trolled retrospective study reported a higher incidence of
monly used for prompt withholding of IV iron therapy in bacteremia with iron sucrose than with ferric gluconate.612
patients on maintenance dialysis. Other studies have failed to show a significant effect of IV
iron dosing or iron status (using serum ferritin) on bacte-
Side Effects of IV Iron. Iron sucrose, lower-molecular- remia, mortality, infection, or hospitalization.522,600,613,614 On
weight iron dextran, and ferric carboxymaltose have excel- the other hand, a later observational study using a very
lent track records for both safety and tolerability. large database found that bolus administration of higher
Hypersensitivity reactions (erythematous rash and urticaria) doses of IV iron was associated with higher risks for infection-
are rare and their intensity is usually mild or moderate. Lack related hospitalizations and death, particularly in patients
of recurrence after rechallenge indicates that most of these undergoing dialysis with catheters rather than arteriovenous
events are not due to immunologic reactions. Severe fistulas or grafts.615 Despite the lack of proof of significant
life-threatening allergic reactions are a major problem with effects on the rates of infections, cardiac events, and mortal-
the higher-molecular-weight iron dextran, prompting its ity, long-term toxicities and, in particular, the possible con-
removal from European and U.S. markets. The use of a test sequences of oxidant damage due to free radical generation
dose is still required for iron dextran in the United States, are still a concern.604,616 Unfortunately no large outcome
but the European Medicines Agency no longer recom- studies have been performed so far to prospectively test the
mends it.592 A retrospective study by Chertow and colleagues efficacy and safety of iron replacement strategies, either in
examining more than 50 million doses of IV iron demon- the short or the long term.617 An ongoing trial in the United
strated the higher risk of reactions with higher-molecular- Kingdom, comparing proactive high-dose IV iron therapy
weight iron dextran and found that rates of serious events with reactive low-dose therapy in 2080 patients new to dialy-
associated with lower-molecular-weight iron dextran were sis, will assess the impact of both regimens on mortality and
similar to those seen with the other forms of IV iron cardiovascular events.618
(≈1/200,000).568,569 A study from the FDA,593 using data
obtained from the administration’s Adverse Event Report- Iron Therapy in Patients with CKD. Iron therapy in CKD
ing System (AERS) and other U.S. databases, was unable to should be guided by iron status test results and clinical
provide firm data on the relative safety of the four IV prepa- considerations and needs to take into account the potential
rations marketed in the United States owing to incomplete benefits of avoiding or minimizing blood transfusions, ESA
brand information on these reports, but it did confirm that use, and anemia-related symptoms against the risk of poten-
allergic reactions have been reported for all brands.594 tial harm (Table 57.2).9 Iron tests should be performed
Chertow and colleagues estimated absolute rates of life- monthly in the initial phase of ESA treatment and every 3
threatening reaction per million doses of 0.6 for iron months thereafter.10,11 As discussed in detail previously, a
sucrose, 0.9 for sodium ferric gluconate complex, 3.3 for target of serum ferritin concentration higher than 200 ng/
lower-molecular-weight iron dextran and 11.3 for higher mL and TSAT value greater than 20% or a CHr value higher
molecular weight iron dextran.569 However, a later system- then 29 pg/cell has been used for patients on dialysis.10,11
atic review highlighted the lack of properly conducted and The KDIGO guideline recommends using IV iron if an
Table 57.2 Current Anemia Guidelines and Position Statements Regarding Iron Administration
KDIGO Clinical Practice 2.1.1: When prescribing iron therapy, balance the potential benefits of avoiding or minimizing blood
Guideline (International) transfusions, ESA therapy, and anemia-related symptoms against the risks of harm in individual
patients (e.g., anaphylactoid and other acute reactions, unknown long-term risks). (Not Graded)
2.1.2: For adult CKD patients with anemia not on iron or ESA therapy we suggest a trial of IV iron (or
in CKD ND patients alternatively a 1-3 month trial of oral iron therapy) if (2C):
• An increase in Hb concentration without starting ESA treatment is desired* and
• TSAT is ≤30% and ferritin is ≤500 ng/mL (≤500 µg/L)
2.1.3: For adult CKD patients on ESA therapy who are not receiving iron supplementation, we suggest
a trial of IV iron (or in CKD ND patients alternatively a 1-3 month trial of oral iron therapy) if (2C):
• An increase in Hb concentration† or a decrease in ESA dose is desired‡ and
• TSAT is ≤30% and ferritin is ≤500 ng/mL (≤500 µg/L)
KDOQI Commentary (United • We believe that the degree of caution expressed by KDIGO is not supported by the available
States) evidence and could have negative effects, such as sustained iron deficiency anemia, higher ESA
dose requirements, and increased blood transfusions.
• We therefore believe that a therapeutic trial of IV iron could be considered when TSAT is low
(≤30%), even if ferritin concentration is above 500 ng/mL.
• There is insufficient evidence upon which to base a recommendation for an upper ferritin limit
above which IV iron must be withheld.
• A decision to administer iron in the setting of high ferritin would require weighing potential risks
and benefits of persistent anemia, ESA dosage, comorbid conditions, and health-related QoL. In
accordance with KDIGO recommendations, Hb response to iron therapy, TSAT, and ferritin
should be monitored closely and further iron therapy titrated accordingly.
CSN Commentary (Canada)§ • There is good evidence (1B) to support the administration of iron in adult CKD patients when the
TSAT and ferritin thresholds are above 20% and 200 ng/mL. A therapeutic trial of iron can be
considered in those where an increase in Hb or reduction of ESA or avoidance of ESA and
transfusion is desired, while recognizing that an increase in hemoglobin is less likely when TSATs
are >30% and ferritins are >500 ng/mL.
• However, as opposed to the KDIGO anemia guideline, the CSN anemia work group feels the
current evidence does not permit a clear delineation for an upper limit of TSAT or ferritin levels.
*Based on patient symptoms and overall clinical goals, including avoidance of transfusion, improvement in anemia-related symptoms, and
after exclusion of active infection.
†
Consistent with Recommendations #3.4.2 and 3.4.3.
‡
Based on patient symptoms and overall clinical goals including avoidance of transfusion and improvement in anemia-related symptoms, and
after exclusion of active infection and other causes of ESA hyporesponsiveness.
§
Quoted material is excerpted to focus on hemodialysis; ferritin units for CSN commentary converted to ng/mL.
CKD, Chronic kidney disease; CKD ND, non–dialysis-dependent CKD; CSN, Canadian Society of Nephrology; ESA, erythropoiesis-
stimulating agent; Hb, hemoglobin; IV, intravenous; KDIGO, Kidney Disease: Improving Global Outcomes; KDOQI, Kidney Disease
Outcomes Quality Initiative; QoL, quality of life; TSAT, transferrin saturation.
From Weiner DE, Winkelmayer WC: Commentary on “The DOPPS practice monitor for US dialysis care: update on trends in anemia
management 2 years into the bundle”: iron(y) abounds 2 years later. Am J Kidney Dis.62:1213-1220, 2013; quoted material from
Kidney Disease Improving Global Outcomes (KDIGO) Anemia Work Group: KDIGO clinical practice guideline for anemia in chronic
kidney disease. Kidney Int Suppl. 2:279-335, 2012; Kliger AS, Foley RN, Goldfarb DS, et al: KDOQI US Commentary on the 2012
KDIGO clinical practice guideline for anemia in CKD. Am J Kidney Dis. 62:849-859, 2013; and Moist LM, Troyanov S, White CT, et al:
Canadian Society of Nephrology commentary on the 2012 KDIGO clinical practice guideline for anemia in CKD. Am J Kidney Dis 62:
860-873, 2013.
increase in Hgb concentration or a decrease in ESA require- studies showed that an intensive IV iron administration pro-
ments is aimed for, if serum ferritin < 500 ng/mL and TSAT tocol (125 mg ferric gluconate with each of eight hemodi-
< 30%.9 For patients with ND-CKD and patients undergoing alysis sessions) can significantly reduce ESA dosing
peritoneal dialysis, target values of more than 100 ng/mL requirements.629,630 A Cochrane systematic review has pro-
for serum ferritin and higher than 20% for TSAT should be vided additional support to the ESA-sparing effects of IV
used. The objective of iron therapy in CKD is to abolish iron.562 Shirazian and associates have noted that ESA-sparing
overt and/or functional iron deficiency, because it reduces effects of IV iron could easily be demonstrated when there
erythropoietic response to and effectiveness of ESAs. The was a high prevalence of iron deficiency and low usage of
response to ESAs can be optimized by the simultaneous use IV iron.619 However, they suggest that most of the benefits
of IV iron, which enables a significant reduction in ESA of IV iron in reducing ESA use have already been achieved,
dosing.619 Several studies conducted in the early and late given that 60% to 80% of patients on dialysis in the United
1990s demonstrated that IV iron therapy is associated with States are being treated with IV iron and that it is not clear
significant ESA dose reductions.562,603,620-628 The DRIVE (Dial- how much additional ESA dose reduction could be obtained
ysis Patients Response on IV Iron with Elevated Ferritin) with more intensive IV iron regimens.
Given the potential adverse effects of ESAs (see later) the resolved, and patients could easily be maintained at Hgb
latest KDIGO anemia guideline mentions explicitly that the values above those that had to be accepted when rRBC
desire to avoid or minimize ESAs can influence the deci- transfusions were the only viable option of anemia manage-
sions about iron use9 (see Table 57.2).9 ment. Androgen therapy, which had been associated with
As shown in Table 57.1, several forms of IV iron are avail- significant side effects, could also be abolished. Because of
able worldwide. Although they have important differences these obvious benefits, the use of epoetin soon became
in formulation and dosing, no convincing evidence has routine and the workup for anemia is considered part of the
been provided about superiority of one form over the others management program of patients in all stages of CKD
in the setting of CKD. The REPAIR-IDA trial demonstrated (Figure 57.9). If the workup reveals no reasons for anemia
that a regimen of two doses of 750 mg of ferric carboxymalt- other than EPO deficiency associated with CKD and in par-
ose in 1 week was not inferior to up to five infusions of iron ticular has ruled out iron deficiency, ESA therapy provides
sucrose in 14 days for anemic subjects with ND-CKD.581 Use an option to correct anemia in almost all patients. However,
of larger doses of IV iron rather than lower maintenance despite the apparent advantages, formal evidence of a posi-
doses does not appreciably affect cardiovascular morbidity tive long-term benefit has never been established.
and mortality in hemodialyzed patients.631 Several lines of indirect evidence suggested that correct-
Some studies have suggested that the addition of ascorbic ing or ameliorating anemia could reduce or at least mitigate
acid to the therapeutic regimen of patients treated with ESA the rate of left ventricular hypertrophy, a frequent complica-
and iron has beneficial effects, although none was rigor- tion in CKD clearly associated with poor prognosis (see
ously conducted to provide definitive evidence.632,633 Limited preceding discussion). Together with the apparent lack of
evidence suggests that ascorbic acid may be pro-oxidant adverse effects of ESA therapy and the contention that
and may increase cytokine levels.634 A systematic review and higher Hgb concentrations might lead to improved HRQOL
meta-analysis concluded that there is evidence, in a limited and physical function, this evidence led to an increase in
number of small studies, that use of ascorbic acid results in Hgb target values. In addition, treatment was expanded to
increased Hgb concentrations, improves transferrin satura- those patients not yet on dialysis, in whom anemia is
tion, and reduces EPO utilization.635 However, use of ascor- generally less severe than in those on dialysis, because avoid-
bic acid is not recommended in either the KDOQI or ance of anemia rather than late correction was intuitively
KDIGO guidelines.10 considered the most appropriate strategy to improve
prognosis and quality of life. Unfortunately, however, for a
EFFICACY AND SAFETY OF ANEMIA MANAGEMENT long time the true nature of the relationship between
WITH ESAS AND IRON long-term reductions in Hgb concentrations and adverse
The change in the condition of patients on maintenance outcomes was not adequately tested in prospective interven-
dialysis following the advent of rhEPO was impressive and tional trials. Few studies have actually compared ESAs
obviously advantageous. Transfusion requirements declined, against placebo, and those trials testing two different Hgb
iron overload due to previous RBC transfusions gradually target ranges have usually been inadequately powered.598
CKD
Stages 1–5
Yes
Check Hb
No ≤13.0 (men)
No workup or
≤12.0 (women)
Yes
CBC, indices, retics;
Workup iron: TIBC, Fe, TSAT;
serum ferritin
Figure 57.9 Flowchart for the evaluation of
No Fe No Further
Normal? the patient with chronic kidney disease (CKD)
deficiency? hematology workup and anemia. CBC, Complete blood count; Fe,
iron; Hb, hemoglobin; TIBC, total iron-binding
Yes Yes Blood loss,
hemoglobinopathy, capacity; TSAT, transferrin saturation. (Modified
vitamin B12, folate from Lankhorst CE, Wish JB: Anemia in renal
Treat with ESA Treat with iron disease: diagnosis and management. Blood Rev
if indicated
24:39-47, 2010. Adapted from K/DOQI clinical
practice guidelines and clinical practice recommen-
dations for anemia in chronic kidney disease in
Anemia not corrected Anemia corrected: Periodic follow-up
adults. Am J Kidney Dis 47[Suppl 3]:S1-145, 2006.)
Meanwhile, evidence from several larger RCTs became better 36-Item Short Form Health Survey (SF-36) vitality
available,635a suggesting that normalization of Hgb concen- score in the higher Hgb than in the lower Hgb group.
trations with ESAs is associated with limited benefit and Adverse event rates were also similar, except that rates of
relevant harm. skeletal pain, surgery, and dizziness were higher in the lower
arm, whereas those of headache and cerebrovascular events
Trial Overview were slightly higher in the higher arm.
Since 1989 slightly more than 25 RCTs using ESAs in patients Thus, neither trial provided any evidence in favor of nor-
with CKD have been published, in which either different malization of hemoglobin concentrations in patients on
target Hgb concentrations were compared or ESA treat- dialysis. However, because the prognosis, extent of comor-
ment was compared with placebo. Approximately half of bidities, and hemodynamic and metabolic milieu of patients
these trials were conducted in patients on dialysis, the other receiving dialysis are so different from those of patients with
half in patients with ND-CKD. Overall approximately 11,000 ND-CKD, the benefit of anemia correction was further
patients have been enrolled in these trials, more than 4000 tested in ND-CKD in three other studies.
of whom were involved in one study, the Trial to Reduce The CREATE (Cardiovascular Risk Reduction by Early
Cardiovascular Events with Aranesp Therapy (TREAT).636 Anemia Treatment with Epoetin Beta) trial was conducted
The number of patients in the other trials varied between in Europe, Mexico, and Taiwan.640 It enrolled approximately
fewer than 20 to approximately 1400.10,11 Several small trials 600 patients with an eGFR of 15 to 35 mL/min and an Hgb
conducted until 1997 compared ESA therapy with placebo. concentration of 11 to 12.5 g/dL. Patients were randomly
Thereafter, only treatment strategies testing two different assigned to a treatment arm in which epoetin beta therapy
ESA regimens were performed until TREAT was designed was started immediately to achieve Hgb concentrations of
as the first large trial to compare ESA therapy with placebo 13 to 15 g/dL or to an arm in which treatment with epoetin
in patients with diabetes and CKD who were not undergoing was not initiated before Hgb had dropped to below 10.5 g/
dialysis. dL; the target Hgb in this second arm was 10.5 to 11.5 g/
dL. The primary end point was a composite of eight
Large Randomized Controlled Trials. The U.S. Normal cardiovascular events, which included “the time to a first
Hematocrit Trial was the first to test whether normalization cardiovascular event, including sudden death, myocardial
of hemoglobin concentrations improves the prognosis of infarction, acute heart failure, stroke, transient ischemic
patients on dialysis.637 It was hypothesized that any presumed attack, angina pectoris resulting in hospitalization for 24
benefit would be most obvious in patients with cardiac hours or more or prolongation of hospitalization, complica-
disease and, therefore, the trial enrolled slightly more than tion of peripheral vascular disease (amputation or necro-
1200 hemodialysis recipients who had congestive heart sis), or cardiac arrhythmia resulting in hospitalization for 24
failure or ischemic heart disease. The target hematocrit in hours or more.”640 The study did not show a significant dif-
the higher arm was 42%, and in the lower arm 30%. The ference in the time to event between the treatment arms.
primary end point was a composite of death and first nonfa- Some dimensions of HRQOL were improved in the arm
tal myocardial infarction. The study was terminated early with earlier treatment and higher target, but unexpectedly,
after 29 months because more patients in the higher arm time to dialysis was significantly shorter in this treatment
had reached the primary end point. Although the difference arm. One of the limitations of the trial was that the observed
did not reach statistical significance, study termination was event rate was much lower than the anticipated event rate,
recommended because it was obvious that the original yielding lower than expected statistical power.
hypothesis, that the higher hematocrit target was of benefit, The CHOIR (Correction of Hemoglobin and Outcomes
could not be proven. In addition, the incidence of vascular in Renal Insufficiency) study, conducted in the United
access thrombosis was significantly higher in the higher States, had a similar design but enrolled patients with more
target hematocrit arm. Self-reported physical function score comorbid disease and yielded different conclusions.641 More
improved at higher hematocrits, but importantly there was than 1400 patients with eGFR values 15 to 50 mL/min and
no significant difference between the two treatment arms for Hgb concentrations below 11 g/dL were randomly allo-
this parameter. A later analysis, which included end point cated to receive epoetin alfa to achieve one of two different
events that the data safety monitoring committee had not yet target Hgb values, 13.5 or 11.3 g/dL. The primary end point
considered when recommending termination of the study, was a composite of death, myocardial infarction, hospitaliza-
also did not reveal a significant difference, and the rates of tion for congestive heart failure, and stroke. The trial was
events occurring during 1-year of follow-up after study termi- terminated when significantly more patients in the higher
nation were similar in the two treatment arms.638 Hgb arm experienced at least one cardiovascular event.
A second large trial in ESKD included almost 600 patients Separate analysis of the four components of the combined
new to hemodialysis without symptomatic heart disease end point revealed trends for more frequent hospitaliza-
and left ventricular dilation.639 Patients were randomly tions for heart failure and more frequent deaths but no
assigned in a double-blind fashion to an Hgb treatment difference in the rates of myocardial infarction or stroke. In
target of either 13.5 to 14.5 g/dL or 9.5 to 11.5 g/dL. The addition, there was a trend toward more rapid progression
primary end point was a change in left ventricular volume of kidney disease in the higher Hgb target group. However,
index, on the assumption that raising the Hgb concentra- a meta-analysis of available studies support an effect of ESA
tion would prevent the progression of left ventricular hyper- on the progression of CKD.642 Unlike in the CREATE trial,
trophy. However, changes in left ventricular volume index twofold to threefold higher doses of epoetin were needed
were similar for the two treatment groups. The only differ- in the CHOIR study to achieve and maintain similar Hgb
ence among a number of secondary outcomes was a values. Interestingly, a post hoc analysis showed that the risks
associated with the higher Hgb target were not apparent Any benefit of higher Hgb for HRQOL appears modest
among subgroups with higher mortality risk.643 on average once Hgb concentrations above about 10 g/dL
In contrast to the other four large trials, the TREAT (Trial are reached. Transfusion rates are lower with higher
to Reduce Cardiovascular Events with Aranesp Therapy) was Hgb,648,649 but it is also clear that attempts to normalize Hgb
designed to test the effect of ESA in comparison with by no means eliminate transfusion requirements. Moreover,
placebo in a sufficiently powered study. More than 4000 the actual benefit from avoiding RBC transfusions is difficult
patients with CKD (eGFR 20 to 60 mL/min/1.73 m2) and to determine in individual patients, although the risk of
type 2 diabetes, and an Hgb concentration below 11 g/dL sensitization in prospective transplant recipients should be
were randomly assigned to receive either darbepoetin with strongly considered.650
a treatment target of 13 g/dL or placebo.636 In order to Whether the balance of the risks and benefits of ESA
avoid development of severe anemia in the placebo-treated therapy depends on the patient’s responsiveness remains
group, a rescue protocol was established, according to which unclear. In treatment protocols driven by a target Hgb
darbepoietin was administered when Hgb fell below 9 g/dL. range, hyporesponsiveness leads to the use of higher doses
The study was double blinded. There were two primary end and is associated with a greater likelihood of adverse events,
points, a cardiovascular composite end point and a renal but whether ESAs play a causal role remains unclear. A
composite end point, including death or initiation of main- secondary analysis of the CHOIR study suggested that high
tenance dialysis. The trial showed no difference in the com- ESA doses rather than high Hgb concentrations are associ-
posite renal or cardiovascular end points, but analysis of the ated with poor outcomes.379,643 In the TREAT, the response
components of the primary end point revealed a significant, to the first two weight-based doses of darbepoetin was a
twofold higher risk of stroke in the darbepoetin arm. As an significant predictor of poor prognosis, with patients in the
additional safety signal, the number of deaths attributed to lowest quartile of ESA responsiveness having higher rates of
cancer tended to be higher in the treatment arm, albeit not the composite cardiovascular end point or death.651 However,
significantly, and in a subgroup of approximately 350 because “hyporesponders” could be identified only among
patients with a history of malignancy, all-cause mortality the treated patients, it is unclear whether their poor prog-
tended to be higher and significantly more deaths were nosis was affected by ESA therapy.
attributed to cancer. These findings were consistent with The global KDIGO guideline for anemia in CKD takes
some findings in ESA RCTs in patients with cancer, which these considerations into account.9 Careful balancing of the
showed higher mortality and more rapid progression of risks and benefits of ESA and iron therapy is an overarching
malignancy in patients treated with ESA for chemotherapy- recommendation. In patients not undergoing dialysis the
related anemia.644 Patients in the darbepoetin arm of the guideline recommends that a drop of Hgb value to less than
TREAT received fewer transfusions and showed a larger 9 g/dL be avoided by initiation of ESA when the Hgb is
mean change in the Functional Assessment of Cancer between 9 and 10 g/dL. In general, ESA should not be used
Therapy: Fatigue (FACT-F) score. to maintain Hgb concentrations above 11.5 g/dL, and there
is a strong recommendation against intentionally raising the
Risk/Benefit Relationship and Target Hemoglobin Recom- Hgb above 13 g/dL. However, individualization appears
mendations. In summary, evidence from well-designed, appropriate, as some patients may have improvements in
larger RCTs indicate that raising Hgb to normal or near- quality of life with Hgb values above 11.5 g/dL and are
normal values with ESAs does not enhance survival or reduce prepared to accept an increased risk.
the rate of cardiovascular events in patients with ND-CKD or In the United States, a major change in payment for
ESKD but is associated with risk for harm.645 These results are dialysis and related services has resulted in bundling of
consistent also with another large trial in patients with heart payments for laboratory services and IV medications
failure, many of whom had CKD.646 Almost all studies showed and their oral equivalents. Together with the previously
increased rates of thromboembolic events, but for unknown mentioned results from clinical trials and subsequent
reasons, other risks are not consistent across different changes in drug labeling from the FDA, these payment
studies. Although the CHOIR study, for example, suggested changes have produced measurable reductions in the
a mortality risk,641 this finding was not confirmed in TREAT.636 use of ESAs and Hgb levels and have resulted in higher rates
Also, a negative impact on the time to dialysis, as found in of transfusion in patients on maintenance dialysis.652 The
the CREATE trial,640 was not found in the TREAT. The U.S. experience may not be directly applicable to other
TREAT, on the other hand, found an increased incidence of countries.653
stroke,639 and although another study had previously
reported a slightly higher number of strokes in a higher Hgb RED BLOOD CELL TRANSFUSION
treatment arm,646 neither the CREATE trial nor the CHOIR When large RCTs questioned the safety and overall benefit
study found differences in stroke rates.640,641 These inconsis- of ESAs and of targeting higher Hgb concentrations, an
tencies may point toward important yet unrecognized factors appreciable increase was observed in the proportion of
that determine the side effect profile of ESAs. Despite inten- patients having Hgb values less than 10 g/dL, which, in
sive investigation, it has not been possible so far to identify conjunction with stable transfusion rates for this patient
characteristics that distinguish patients in whom stroke subgroup, translated into an increase in the absolute
developed during ESA therapy in the TREAT.647 Whether number of transfusions.648 As shown in Figures 57.3and
any of the observed adverse events are related to the actual 57.10, transfusion rates for U.S. patients on maintenance
achieved Hgb values, to indirect effects of an increase in dialysis were 2.9% in 2011 and 3.0% in 2012. Interestingly,
erythropoiesis, or to direct, hemoglobin-independent effects transfusion rates in patients with ND-CKD also rose signifi-
of ESAs is unknown.643 cantly from 2002-2003 to 2008 (see Figure 57.10).649
20.0 12
Hb 10 g/dL
Transfusion rate per 100 patient-months

18.0
10
Percent of Patients Hb 10 g/dL
16.0
14.0 8
12.0
Raw
10.0 6
8.0
4
6.0 Adjusted
4.0 2
2.0 Hb 10 g/dL
0
0.0
1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010
1 month (June) 3 month average (Apr-June)

A B
60
CKD
Transfusion rate (per 100 person-years)
50 CKD w/diagnosed anemia

Transition to ESRD
40
30
20
10
0
2002 2003 2004 2005 2006 2007 2008
C Year
Figure 57.10 Red blood cell transfusion in chronic kidney disease (CKD). A, Proportion of patients with a single monthly or 3-month
average hemoglobin (Hb) concentration of ≤10 g/dL, 1999-2010. B, Unadjusted and adjusted (for age, sex, race, primary cause of end-stage
kidney disease, hospitalization days, and dose of erythropoiesis-stimulating agent) 6-month transfusion rates for patients with Hb levels less
than 10 and equal to or greater than 10 g/dL (1999-2010). C, Annual red blood cell transfusion rates per 100 person-years (2002–2008) for
patients with CKD; patients with CKD and diagnosed anemia, and patients with CKD transitioning to end-stage renal disease (ESRD) during
each follow-up year. (A and B from Gilbertson DT, Monda KL, Bradbury BD, et al: RBC transfusions among hemodialysis patients (1999-2010):
influence of hemoglobin concentrations below 10 g/dL. Am J Kidney Dis. 62:919-928, 2013; C from Gill KS, Muntner P, Lafayette RA, et al: Red
blood cell transfusion use in patients with chronic kidney disease. Nephrol Dial Transpl 28:1504-1515, 2013.)
Transfusion is associated with development of alloanti- receive transfusions. We agree with the current consensus
bodies and HLA sensitization,654 which has important nega- that blood transfusion should be avoided if possible.650
tive consequences for donor matching of patient candidates Because transplantation waiting times exceed life expec-
for renal transplantation. HLA sensitization also increases tancy throughout most of the United States and much of
graft rejection and diminishes graft survival. It is unlikely the developed world, patients can ill afford a procedure
that blood transfusion has any benefit on subsequent (i.e., transfusion) that offers modest if any benefit and that
allograft function. Although the published literature seems can further lower the likelihood of ever receiving a kidney
to have mixed results, patients who received transfusions transplant.
and who developed alloantibodies were less likely to undergo Relatively common complications of RBC transfusions
transplantation. It is unreasonable and potentially mislead- are febrile or urticarial/allergic (immediate hypersensitiv-
ing to compare patients who received transfusions and did ity) reactions. Less common complications include acute
not develop alloantibodies with all patients who did not and delayed hemolytic transfusion reactions, hypotensive
transfusion reactions, transfusion-associated dyspnea, Several factors contribute to increase the risk of bleeding
transfusion-associated circulatory overload, transfusion- in patients with CKD (Figure 57.11).662 It has long been
related acute lung injury, posttransfusion purpura, and noted that bleeding in uremic patients occurs despite
transfusion-associated graft-versus-host disease. Additional normal or elevated circulating values of coagulation
complications of RBC transfusion include potential trans- factors.655 This observation suggested that platelet abnor-
mission of known and unknown infectious agents, and iron malities are the primary cause of the bleeding diathesis. The
overload. function of platelets is often impaired (thrombasthenia)
whereas the number of circulating platelets is generally
normal, with perhaps a tendency to decrease the longer
DISORDERS OF HEMOSTASIS IN CHRONIC patients have been undergoing dialysis.663 Thrombopoietin
values are elevated in patients who are on maintenance
KIDNEY DISEASE
hemodialysis and being treated with rhEPO but do not cor-
relate with platelet counts.663,664 Evidence for platelet dys-
BLEEDING AND CHRONIC KIDNEY DISEASE
function includes elevated bleeding time,655 diminished
Excessive bleeding has long been recognized as an impor- aggregation response to ADP and epinephrine,665 reduced
tant complication of the uremic state.655-657 This was particu- ristocetin-induced platelet agglutination,666 and prolonged
larly true prior to the advent of dialysis and the availability closure time with the Platelet Function Analyzer (PFA,
of rhEPO. Events may be as minor as epistaxis, excessive Siemens Medical Solutions).667,668
bleeding with tooth brushing, and easy bruisability. More The most consistent abnormality in platelet function in
severe, clinically relevant bleeding episodes tend to occur uremia is an impaired interaction of platelets with the vascu-
with trauma or after invasive procedures rather than spon- lar subendothelium.655 As a result, platelet adhesion and
taneously.658 Before the availability of routine dialysis, cata- aggregation are hindered. The cause of this dysfunction is
strophic gastrointestinal hemorrhage was the major cause incompletely understood and could be related to abnormali-
of death with uremia.655 Bleeding is frequently a predictor ties of the vessel wall, platelets, or plasma constituents. As for
of increased mortality risk or complications.659 the vessel wall, it appears that its function may be altered in
uremia. In particular, endothelial production of NO, a pow-
PATHOPHYSIOLOGY erful platelet inhibitor, has been noted to be increased,669-671
Traumatic disruption of the endothelial lining of blood resulting in higher concentrations of cyclic guanosine mono-
vessels results in a complex and coordinated response aimed phosphate and reduction of platelet responsiveness. In
to maintain vascular integrity and prevent bleeding. The first uremic rats, treatment with an NO inhibitor partially restores
line of defense in hemostasis is represented by platelets, platelet function.672 Interestingly, guanidinosuccinic acid,
which specifically interact with ligands exposed as a conse- long postulated to play a role in uremic platelet dysfunction,
quence of endothelial damage. These ligands, which include has been found to upregulate NO production by the vascular
collagen, fibronectin, laminin, thrombospondin, and von endothelium.673 Prostaglandin I2 (PGI2), which is released by
Willebrand factor (vWF), promote the adhesion of platelets endothelium, is increased in patients with CKD and increases
to subendothelium and their activation. Activated platelets bleeding times674 and probably plays a role in reducing plate-
further release adhesive ligands stored in their α-granules, let aggregability.674
such as vWF, fibrinogen, thrombospondin, fibronectin, and The platelet itself is intrinsically altered in uremia. For
vitronectin, and promote the activation of additional plate- example, the content of serotonin and ADP is reduced in
lets by releasing aggregating agents such as thromboxane A2 uremic platelet granules.665 Secretion of mediators may also
(TXA2) and adenosine diphosphate (ADP). An occlusive be impaired, although this effect may be a function of
plug is eventually formed by deposition of platelets on col- repeated activation during hemodialysis.675 Platelet recep-
lagen fibers. The surfaces of platelets play an essential role tors that play a critical role in adhesion to the vessel wall
in supporting the coagulation cascade in plasma, which and aggregation, like those for GP1b and GPIIb-IIIa, are
results in the activation of thrombin, conversion of fibrino- probably not significantly reduced in quantity in uremia.676
gen to fibrin, and formation of the fibrin plug, which is sta- However, interaction of the receptors with vessel wall pro-
bilized by factor XIIIa. Generation of thrombin further teins may be abnormal.677 In particular, activation of
enhances the activation of platelets and upregulates glyco- GPIIb-IIIa to facilitate its adhesion to vWF may be impaired.678
protein (GP) receptors like those for GPIb-IX-V and The platelet cytoskeleton may be altered, with diminished
GPIIb-IIIa. Several systems play an important role in limiting actin incorporation and suboptimal intracellular trafficking
the extent of coagulation activation and thrombus forma- of molecules.679-681
tion. Nitric oxide (NO) and prostacyclin limit the activation Although the platelet itself is not entirely normal in
of platelets. Tissue factor pathway inhibitor (TFPI), the uremia, it appears that a more important pathogenic factor
protein C and S system, and antithrombin turn off activated in platelet dysfunction may be the effect that uremic plasma
coagulation factors at various steps of the coagulation has on platelet responsiveness. Platelets from normal indi-
cascade. The fibrinolytic system is also crucial in both limit- viduals develop impaired adhesive function on exposure to
ing the growth of thrombi and promoting their organization uremic plasma.682 In contrast, platelets from uremic subjects
and removal. Fibrin digestion is mediated by plasmin, which regain some function on exposure to normal plasma.682
is circulating in plasma as plasminogen, an inactive precur- Certain molecules with molecular weights that preclude
sor. Conversion of plasminogen to plasmin is promoted by adequate clearance with hemodialysis accumulate in uremia
tissue plasminogen activator (t-PA) and inhibited by plas- and may contribute to platelet dysfunction.683 A variety of
minogen activator inhibitors (PAI-1 and PAI-2).660,661 toxins, including quinolinic acids and guanidine substances,
Extrinsic system
Intrisic system
Tissue injury
XII XIIa
XI XIa Tissue thromboplastin

Accumulation of
IX IXa VIIa VII anticoagulants
Coagulation in patients with
cascade X Xa X renal failure
AT Va V
XIII
Prothrombin (II) Thrombin (lla)
XIIIa
Fibrinogen Fibrin Fibrin peptides
Disturbed composition
Plasminogen Plasmin of -granules
Activation of the tPA

fibrinolytic system Dysregulated
T
arachidonic and
PAI-1
Platelets prostaglandin
Anemia: metabolism
Reduced platelet vessel wall interaction Reduced
Reduced ADP release/PIG2 inactivation binding of T
Reduced scavenging of NO vWF and
fibrinogen
Changed Ca
metabolism
GP Ib reduced
Increase of
vasoactive
substances
(i.e., NO)
Decreased function
Vessel wall of Gp IIb/IIIa
E E
V
Figure 57.11 Factors involved in the increased risk of bleeding in patients with renal failure. Roman numerals with/without lower case
letters indicate clotting factors; ADP, adenosine diphosphate; AT, Anti-thrombin; Ca++, calcium ion; E, endothelium; GP, glycoprotein; NO, nitric
oxide; PIG2, prostaglandin I 2; T, thrombocyte; tPA, tissue-type plasminogen activator; V, vessel; vWF, von Willebrand factor. (From Lutz J,
Menke J, Sollinger D, et al: Haemostasis in chronic kidney disease. Nephrol Dial Transpl 29:29-40, 2014.)
have been implicated.655 In addition, a role for hyperpara- Anemia is an important contributor to uremic platelet
thyroidism has been suggested. Benigni and colleagues dysfunction.693 During normal circulation, erythrocytes tend
found parathyroid hormone to impair platelet aggregation to force the flow of platelets radially, away from the center
induced by a variety of substances.684 Hyperparathyroidism of flow and toward the endothelial surfaces. When vascular
may affect platelet function by elevating intracellular injury occurs, platelets are in closer apposition to the vessel
calcium concentrations via channels that are sensitive to wall, facilitating platelet adherence and activation by vessel
calcium channel blockers like nifedipine.685 wall constituents such as collagen. With anemia, more plate-
It is generally accepted that dialysis reduces uremic platelets circulate in the center of the vessel, further from endo-
let dysfunction and the risk for bleeding. But dialysis does thelial surfaces, hindering efficient platelet activation.693 In
not completely eliminate the problem. Moreover, hemodi- addition, anemia may contribute to platelet dysfunction
alysis may induce a transient worsening in platelet function. because release of ADP by erythrocytes normally stimulates
Sloand and Sloand measured a variety of indicators of plate- platelet interaction with collagen.694,695 Treatment of anemia
let function immediately before and after treatments and may help reverse platelet dysfunction, as both transfusion
noted a transient decrease of platelet membrane expression of blood693,696 and ESA therapy697 have been found to be
of GPIb after hemodialysis. Ristocetin responsiveness was beneficial.
impaired after hemodialysis and normalized the day after The plasma content of the major adhesive proteins, vWF
treatment.686 Other potential detrimental consequences of and fibrinogen, are normal in uremia. One study showed a
hemodialysis might include the enervating effect of repeated normal distribution of VWF multimers666 while another one
platelet activation,687,688 removal of younger platelets with reported a reduction in high-molecular-weight VWF multi-
greater function,689-691 and impairment of platelet function mers.698 The functional properties of vWF are altered,
from a secondary effect of activated leukocytes.692 however, mostly at the level of the interaction with the
GPIb-IX-V platelet receptors, a key step in the signaling expression of GPIb,655,713 and repaired platelet signal
pathways, which ultimately lead to TxA2 production.699-702 transduction.714
Platelet-derived procoagulant microparticles have been Desmopressin (1-deamino-8-d-arginine vasopressin,
described in CKD,703,704 but owing to inconsistent and unreli- DDAVP) is a synthetic form of antidiuretic hormone that is
able methodologies to measure microparticles in plasma, it often used to treat uremic bleeding. The drug has little vaso-
is not possible at this time to determine their clinical pressor activity and only rarely induces hyponatremia. The
relevance. mechanism of improved platelet function is not completely
known, but enhanced release of larger vWF multimers by
DIAGNOSTIC STUDIES endothelial cells probably plays an important role.715,716
Despite abundant evidence that the bleeding time is an Other factors may include improved platelet aggregation on
unreliable test which has limited value in predicting contact with collagen and increased concentrations of plate-
bleeding complications,705 use of this test is still reported let glycoprotein Ib/IX.717 Given the unreliability of the
in CKD.662 More reliable tests are available, such as bleeding time, it is not a surprise that IV infusion of 0.3 mcg/
platelet aggregation and platelet function analyzer (PFA), kg desmopressin (or 3.0 mcg/kg subcutaneously) produced
although their value in predicting and managing bleeding inconsistent results.715,718-720 DDAVP infusion improves plate-
complications is not yet proven. Thrombin generation let function in vitro and increases plasma concentrations for
assays may help in assessing both hypo- and hyper-coagulable both VWF and Factor VIII.667 DDAVP may also be adminis-
states, but there are so far only limited studies in patients tered by the intranasal route, at a dose approximately tenfold
with CKD.706 greater than that given intravenously.721-723 Repeated admin-
istrations of DDAVP may result in a diminished response
TREATMENT with development of tachyphylaxis, caused by the depletion
The treatment of patients with renal failure experiencing of the endothelial stores of vWF multimers.724,725
bleeding episodes requires (1) an assessment of the severity Other treatments for uremic bleeding include infusion of
of blood loss, (2) hemodynamic stabilization, (3) replace- cryoprecipitate, a plasma product rich in vWF and fibrino-
ment of blood products as needed, (4) identification of the gen.726,727 There is very little published evidence to support
bleeding source and etiology, and (5) correction of platelet the use of cryoprecipitate, and response appears to be
dysfunction and other factors contributing to the bleeding highly variable. In one study of five patients with active
diathesis (Figure 57.12). The first four aspects are routine bleeding, only two had normalization of bleeding time and
components of clinical care and are not discussed further a favorable clinical outcome after treatment.728 Cryoprecipi-
here; the fifth extends from the previous discussion on the tate use should be reserved for life-threatening bleeding
pathobiology of uremic bleeding. It should be clear, however, due to the risk for infectious complications and limited
that the intensity of interventions to correct uremic platelet availability.
dysfunction hinges on the degree of bleeding severity. Estrogens improve platelet function in both men and
The first aspect of treatment to correct uremic platelet women.729-731 After IV infusion, Livio and associates found
dysfunction is provision of adequate dialysis. Initiation of the beneficial effect of conjugated estrogens to begin early
dialysis will lead to some improvement in thrombasthenia and last for up to 2 weeks.732 The mechanism of action of
and bleeding risk.665,707 The PFA closure time improves in estrogen treatment is not fully known, but it may be related
25% of patients after a dialysis session.708 No studies have to inhibition of vascular NO production, by decreasing pro-
fully elucidated the relative effectiveness of hemodialysis duction of its precursor, l-arginine.733
versus other dialytic modalities, but platelet activation mea- Short-term (6 days) and long-term (3 months) treatments
sured by CD62 expression was increased by hemodiafiltra- with the fibrinolytic inhibitor tranexamic acid were associ-
tion while PLT degranulation products were increased in ated with a reduction in the bleeding time and improved
hemodialysis.709 In any case anticoagulation must be mini- platelet function.734,735 Tranexamic acid may also be benefi-
mized. The relation of dose of dialysis with improvement of cial in the treatment of acute upper gastrointestinal bleed-
platelet function has not been well studied. ing episodes.736
Treatment of anemia with ESAs may be the most effective
treatment of uremic platelet dysfunction (see above). Cases HYPERCOAGULABILITY AND CHRONIC
and associates found that treatment with epoetin alfa, 40 U/
KIDNEY DISEASE
kg intravenously resulted in improvement in several param-
eters of platelet function as the Hgb rose.710 Others have Although bleeding is the most clinically relevant manifesta-
found the same salutary effect of ESA treatment.105,697 tion of the effects of advanced CKD on hemostasis,
Improved platelet function following EPO treatment is most several lines of evidence indicate the presence of a pro-
likely related to the associated changes in blood flow, with thrombotic, hypercoagulable state, which may play a role in
platelets moving closer to the vessel walls. However, it is also the atherosclerotic/cardiovascular complications. Deep
possible that EPO treatment itself may directly affect plate- venous thrombosis (DVT) seems to affect predominantly
let function. Tassies and colleagues found that platelet func- CKD patients in younger age, of African American or His-
tion improved in some patients after epoetin treatment was panic background, in association with cardiovascular disease
initiated, before Hgb values increased.711 The authors attrib- and prior surgical interventions.737 The incidence of symp-
uted this effect to an increase in young circulating forms of tomatic venous thromboembolism is moderately increased
platelets, with improved functional characteristics. Other in mild-to-moderate CKD (based on eGFR and albumin-
potential direct beneficial effects of ESA include improved uria) as shown by a study pooling three European and two
platelet intracellular calcium mobilization,712 increased U.S.-based community-based cohorts,738,739 as well as by a
Uremic bleeding suspected or confirmed?

(e.g., gastrointestinal bleeding, ecchymosis, hematuria)
Yes No
Hemodynamically stable? Urgent surgery?

Yes No Yes No
Control of bleeding Can patient tolerate DDAVP Surgery within

or emergency extra fluid? 2 weeks?
surgery needed?
Yes No Yes No
Yes No
Whole blood Packed red blood

cells, or one dose
DDAVP plus
or minus
cryoprecipitate
Did this control Estrogens
and/or
stop bleeding?
One dose DDAVP No Yes Dialysis

plus or minus (first, replete iron, then
cryoprecipitate initiate recombinant
human EPO with target
Did this control hematocrit >30%; second,
and/or stop bleeding? consider initiating dialysis)
Yes No
Monitor hemoglobin and Conjugated estrogens

hematocrit and vital signs regardless of gender
See ‘Dialysis’
Figure 57.12 Algorithm for the management of patients with uremic platelet dysfunction. If at any stage in the algorithm the patient with
uremic platelet dysfunction starts to actively bleed, the clinician should return to the top of the algorithm. This algorithm is not intended to
replace sound clinical judgment or prevent additional consideration of patient factors that could influence management decisions. DDAVP,
desmopressin (1-deamino-8-D-arginine vasopressin; single doses of 0.3-0.4 µg/kg body weight intravenous); EPO, erythropoietin. (From Hedges
SJ, Dehoney SB, Hooper JS, et al: Evidence-based treatment recommendations for uremic bleeding. Nat Clin Pract Nephrol 3:138-153, 2007.)
large population-based study in Denmark.740 The incidence erythrocyte membrane phosphatidylserine externalization
of pulmonary embolism in CKD and ESKD is not precisely possibly playing a role in this procoagulant state.746-749 Phos-
known (it may be particularly common after vascular access phatidylserine externalization may be mediated by uremic
procedures—see Chapter 65), but mortality rates for pulmo- toxins, since it improves after dialysis treatment.750 Despite
nary embolism are substantially higher in patients on the functional platelet defects described above, abnormalities
dialysis than in the general population.741 As described in the soluble coagulation cascade and in some of the natural
above ESA therapy may further increase thromboembolic anticoagulant systems like fibrinolysis generate a hypercoagu-
complications. lable state which may facilitate cardiovascular and thro\mbotic
complications in dialyzed patients.751,752 Complement activa-
EVIDENCE FOR HYPERCOAGULABILITY IN CKD tion may take place during dialysis, with increased expression
As outlined in Figure 57.13, several pathways are altered of tissue factor on peripheral neutrophils and increased pro-
toward hypercoagulability and increased risk of thrombosis duction of granulocyte colony-stimulating factor (G-CSF)
in CKD.662 Activated/hypercoagulable platelets have been resulting in a hypercoagulable state.753
reported in patients with impaired or declining kidney
function,742,743 while other studies have shown increases PHARMACOLOGIC INTERVENTIONS
in soluble markers of activated coagulation and fibrinoly- Treatment of hypercoagulability may expose patients to
sis.744,745 Several markers for thrombin activation (prothrom- additional bleeding complications. A systematic review of
bin fragment F1.2 and thrombin-antithrombin complex) bleeding rates in patients with CKD treated with antiplatelet
and fibrinolysis (D-dimer and plasmin-antiplasmin complex) drugs showed that these agents are effective in reducing
are abnormally elevated in dialyzed CKD patients, with arteriovenous fistula and central venous catheter, but not
Extrinsic system
Intrisic system
Tissue injury
XII XIIa
XI XIa Tissue factor
IX IXa VIIa VII

Coagulation
cascade X Xa X
AT Va V
XIII
Prothrombin (II) Thrombin (lla)
Increase of phosphatidyserine,
XIIIa p-selectin, and fibrinogen
receptor PAC-1
Fibrinogen Fibrin Fibrin peptides
Microparticles:
Plasminogen Plasmin Presentation of
Thrombin-antithrombin (TAT)
phosphatidylserine, tissue
complexes;
tPA factor, contain micro RNAs
Prothrombin fragments
(regulation of platelets?)
12 (F 12) T
PAI-1
Platelets
Stimulation through thrombin,
hypoxia, shear stress, oxidants,
T
IL-1, TNF, -interferon,
Anti-phospholipid desmopressin, endotoxin
antibodies
Decrease of
vasoactive
substances Inhibition of protein C
(i.e., NO) system and of release of tPA,
increased activity of MMP-9
by homocysteine
Vessel wall
E E
G
Figure 57.13 Factors involved in the increased risk of thrombosis in patients with renal failure. Roman numerals with/without lower case
letters indicate clotting factors; AT, Anti-throbin; E, endothelium; G, sub-endothelial connective tissue; IL-1, interleukin-1; MMP-9, matrix
metalloproteinase 9; NO, nitric oxide; PAC-1, monoclonal antibody specific for the activated form of GPIIb-IIIa; PAI-1, plasminogen activator
inhibitor-1; T, thrombocytes; TNF, tumor necrosis factor; tPA, tissue-type plasminogen activator; vWF, von Willebrand factor; ↓, decreased; ↑,
increased. (From Lutz J, Menke J, Sollinger D, et al: Haemostasis in chronic kidney disease. Nephrol Dial Transpl 29:29-40, 2014.)
arteriovenous graft thrombosis.754 No firm conclusions myocardial infarction (MI) was associated with lower mor-
could be reached about possible increases in bleeding rates tality and lower incidence of MI and ischemic stroke with
in patients treated with a single agent, while there was no substantial higher risk of bleeding complications.758 A
an apparent increase in bleeding risk for combination Danish registry study has shown that in high-risk CKD
therapy.754 In patients treated for ischemic stroke, presence patients treatment of atrial fibrillation with warfarin resulted
of CKD was associated with a two-fold increased frequency in measurable reductions in all-cause mortality and in hos-
of clopidogrel resistance (by VerifyNow P2Y12 Assay).755 pitalization for stroke/bleeding.759
Atrial fibrillation is a relatively common occurrence in Novel oral anticoagulants have been approved for use in
patients with CKD and ESKD. The optimal approach to the general population with studies including a variable
prevention of stroke and other embolic complications is fraction (7 to 21%) of subjects with impaired kidney func-
unknown. There are concerns that chronic treatment with tion (eGFR < 50 mL min-1).760 A systematic review and meta-
vitamin K antagonists may worsen vascular calcification.756 analysis showed no significant differences in either
Warfarin dosing is complicated in CKD and ESKD by drug- thrombo-embolic or hemorrhagic complications in CKD
drug interactions, variability in dietary intake and frequent patients treated with either warfarin or novel anticoagu-
administration of antibiotics. The risk-benefit balance of lants.761 A similar study showed significant reduction (com-
warfarin for stroke prevention in advanced CKD and ESKD pared with warfarin) for bleeding complications in patients
is unknown. A recent study showed no reduction in the risk with impaired renal function only for agents with lower
of stroke and higher bleeding risk in dialyzed CKD patients renal excretion (<50%, i.e. apixaban, rivaroxaban and
with atrial fibrillation treated with warfarin.757 However, war- edoxaban).760 However, until properly controlled, random-
farin use to treat atrial fibrillation in patients with CKD post ized trials are conducted in patients with end stage renal
disease, it seems premature to recommend replacing warfa- state. Activation of platelets adhering to dialysis membranes
rin therapy with these newer agents.762 may contribute to leukocyte activation and production of
Dabigatran,763 a direct thrombin inhibitor, apixaban764 reactive oxygen species (ROS).783-789 Different types of syn-
and rivaroxaban,765 two factor Xa inhibitors, have been thetic dialysis membranes have been shown to induce dif-
used in patients with CKD. Limited experience is available ferent degrees of oxidative stress (measured in serum with
for newer agents, like the indirect factor Xa inhibitor the surrogate marker malondialdehyde).790
fondaparinux.766,767 While low molecular weight (LMW) and
unfractionated heparin (UFH) can be reversed with
LEUKOCYTE (MONOCYTE) ACTIVATION
administration of protamine sulphate, newer agents like
fondaparinux have no specific antidotes, although recombi- Several studies have shown elevations in markers of leuko-
nant factor VIIA and antithrombin have been used to cyte and monocyte activation in patients receiving dialy-
reverse novel anticoagulant overdoses.768-770 sis,788,791-793 as well as increased heterotypic aggregation for
The safety of omitting heparinization when dialyzing both leukocytes and lymphocytes.794 Advanced oxidation
patients on chronic anticoagulation therapy with vitamin K protein products (AOPP) carried mostly by serum albumin
antagonists has recently been demonstrated.771 have been identified in the serum of patients receiving dialy-
sis.795 These AOPPs are believed to be end-products of
protein oxidation, whose concentrations are correlated with
HEPARIN-INDUCED THROMBOCYTOPENIA
the severity of uremia, the extent of monocyte activation
HIT can be seen in patients receiving hemodialysis due to (assessed by serum neopterin)796,797 and to the generation
their repeated and frequent exposure to heparin.772,773 The of myeloperoxidase by neutrophils in dialysis patients but
presence of antibodies to the platelet factor 4-heparin not in predialysis conditions.798 AOPP can trigger neutro-
(PF4-H) complex has been associated with arterial and phil activation and respiratory burst, which can be reduced
venous thrombosis and increased mortality,774,775 but other in vitro by N-acetylcysteine.799 Leukocyte 8-hydroxy-2′-
studies have found no correlation between the presence of deoxyguanosine (8-OHdG) is a marker of oxidant-induced
these antibodies and either reduction in platelet counts,776 DNA damage, which is particularly elevated in patients car-
or clinical complications,773,777 or vascular access thrombo- rying a Glutathione S-transferase M1 (GST M1) polymor-
sis.778 An acute thrombotic event in a thrombocytopenic phic dysfunctional variant.605
patient on maintenance hemodialysis or unexpected occlu- Evidence for leukocyte activation and ROS generation
sions of the extracorporeal circuit,779 should prompt a has also been found in patients with ND-CKD .800 Degran-
search for possible HIT. However, the isolated presence of ulation of neutrophils results in release of a variety of
PF4-H antibodies should not by itself lead to either a diag- enzymes and proinflammatory mediators:801,802 some of
nosis of HIT or institution of specific anti-HIT therapies. these mediators, such as heparanase,803 an endoglycosidase
The presence of oversulfated chondroitin sulfate as a pur- involved in the degradation of extracellular matrix, have
poseful contaminant of heparins produced in China, which been linked to the generation of atherosclerotic lesions;
resulted in a large number of adverse events, has also been others, like myeloperoxidase generate hypochlorous acid
associated with increased prevalence of PF4-H antibodies potent microbicidal and oxidant compound. Hypochlo-
but no thrombocytopenia.780 If the presence of HIT is con- rous acid may play a role in activating monocytes, which
firmed based on established criteria,773 all heparin-based produce a whole array of inflammatory cytokines (IL-6,
therapies should be discontinued and the use of direct TNF-α, and IL-1β).
thrombin inhibitors (pelirudin and argatroban) or factor
Xa inhibitors (danaparoid) should be considered. Warfarin
LEUKOCYTE FUNCTIONAL IMPAIRMENT
should not be considered until the resolution of thrombo-
cytopenia and neither should be prophylactic platelet Granulocytes of patients receiving hemodialysis exhibit
transfusions. impaired adhesion to fibronectin, which is more prominent
in conditions of malnutrition.804 Prominent apoptosis is
observed in monocytes of patients with CKD,805 and changes
WHITE CELL FUNCTION IN CHRONIC in monocyte subpopulations (CD16+) are associated with
KIDNEY DISEASE increased soluble proinflammatory markers such as chemo-
kine (C-X3-C motif) ligand 1, or CX(3)CL1.806 Increased
CKD is accompanied by a chronic inflammatory state of production of ROS and accumulation of toxic products
complex pathogenesis, which is believed to be at least in associated with uremia253,254 are likely but not yet proven
part due to an increased generation of oxygen radicals culprits in the generation of a dysfunctional immune
and associated activation of monocytes. Uremic toxins response in patients with CKD. Enhanced susceptibility to
have been blamed as a likely cause of this dysfunctional bacterial or viral infections on the one hand and reduced
state, however with no specifically proven connec- response to hepatitis B vaccine on the other have been
tions.253,254,781,782 For more specific information on the bio- described.807 Functional abnormalities in monocytes and T
logical significance of uremic toxins, see Chapter 54, or the lymphocytes808-810 as well as in natural killer cells811 have been
European Uremic Solutes database (EUTox-db): http:// reported. It has been suggested that such abnormalities may
eutoxdb.odeesoft.com/index.php. The use of particular be representative of a myeloid shift of erythropoiesis similar
dialyzers and dialysates has been associated with intradia- to that observed with aging.812 New dialysis membranes
lytic leukocyte activation and enhanced oxidant stress, designed to reduce immune dysfunction are being devel-
which exacerbate the underlying activated inflammatory oped, with encouraging but still preliminary results.813
207. Madore F, Lowrie EG, Brugnara C, et al: Anemia in hemodialysis

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Hematologic Aspects of 57

ANEMIA OF KIDNEY DISEASE, 1875 DISORDERS OF HEMOSTASIS IN CHRONIC

1.0 threshold of 60 mL/min per 1.73 m2 for both sexes, below

Hemoglobin level <11 g/dL

Percent receiving ESA

1 All Black 1 All Black

Geographic variations in the percentage of patients

1.9 3.3 1.9 3.5 1.9 3.4

Normoxia Proteasomal destruction of HIF-α

OH Binding of hydroxylated HIF to

(A) Normal erythropoiesis

0.42 0.40 0.38 1.00

(B) Elevated EPO levels

0.58 0.57 0.56 1.00

0.25 0.33 0.25 1.00

(D) Ineffective erythropoiesis

0.58 0.36 0.30 0.33

(E) Iron-deficient erythropoiesis HRI

0.58 0.57 0.56 1.00

ERYTHROPOIETIN PRODUCTION AND 1. Serum EPO concentrations are generally equal to or

RBCs Fe loss Duodenum

% with Hgb  9 % with Hgb 10–11 % with Hgb  12

Mean weekly EPO dose (units/week)

12.0 15,000 12.0 15,000

11.5 12,500 11.5 12,500

11.0 10,000 11.0 10,000

10.5 7500 10.5 7500

10.0 5000 10.0 5000

Percent of patients receiving IV iron

450 independently of iron status, this parameter increases in

ferritin,516 is insensitive to dynamic changes in iron status,

Table 57.1 Intravenous Iron Preparations

FDA Approved Not FDA Approved

Transfusion rate per 100 patient-months

1 month (June) 3 month average (Apr-June)

50 CKD w/diagnosed anemia

XI XIa Tissue thromboplastin

Fibrinogen Fibrin Fibrin peptides

Activation of the tPA

Uremic bleeding suspected or confirmed?

Hemodynamically stable? Urgent surgery?

Control of bleeding Can patient tolerate DDAVP Surgery within

Whole blood Packed red blood

One dose DDAVP No Yes Dialysis

Monitor hemoglobin and Conjugated estrogens

XI XIa Tissue factor

IX IXa VIIa VII

207. Madore F, Lowrie EG, Brugnara C, et al: Anemia in hemodialysis

26. Kassebaum NJ, Jasrasaria R, Naghavi M, et al: A systematic analysis

Potrebbero piacerti anche

1.0 threshold of 60 mL/min per 1.73 m2 for both sexes, below

% with Hgb 9 % with Hgb 10–11 % with Hgb 12

207. Madore F, Lowrie EG, Brugnara C, et al: Anemia in hemodialysis

26. Kassebaum NJ, Jasrasaria R, Naghavi M, et al: A systematic analysis