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Anaemia in CKD—treatment standard Iain C. Macdougall †
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Anaemia in CKD—treatment standard Iain C. Macdougall †
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Nephrol Dial Transplant, 2024, 39, 770–777https://doi.org/10.1093/ndt/gfad250
Advance access publication date: 27 November 2023
Anaemia in CKD—treatment standard
TREATMENT STANDARD
†
Iain C. Macdougall
Department of Renal Medicine, King’s College Hospital, London, UK
Correspondence to: Iain C. Macdougall; E-mail: iain.macdougall11@gmail.com
†
Retired.
Watch the video of this contribution at https://academic.oup.com/ndt/pages/author_videos
ABSTRACT
Downloaded from https://academic.oup.com/ndt/article/39/5/770/7452913 by guest on 25 May 2024
Anaemia is one of the most common complications of chronic kidney disease (CKD), having a significant impact on quality of life,
and is also associated with a number of adverse clinical outcomes. Its pathogenesis is multifactorial, caused largely by an inadequate
production of erythropoietin from the diseased kidneys, with iron deficiency, inflammation, shortened red cell lifespan and enhanced
blood loss also being contributory factors. The management of this condition was transformed in the late 1980s by the advent of
recombinant human erythropoietin (epoetin), and treatment paradigms have developed over the last three decades, largely focusing
on a combination of epoetin or its analogues (erythropoiesis-stimulating agents; ESAs) along with iron supplementation, often ad-
ministered intravenously due to increased hepcidin levels limiting iron absorption from the gut. Indeed, in patients with early CKD
and iron deficiency, iron per se may be sufficient to improve the anaemia, delaying the need for ESA therapy. Other causes of anaemia
should be excluded and corrected (if possible) before resorting to treatment with ESAs and iron. More recently, the hypoxia-inducible
factor–prolyl hydroxylase inhibitors have entered the therapeutic arena; these are orally active agents that upregulate endogenous
erythropoietin production as well as a number of iron-regulatory genes which may also enhance erythropoiesis. The latter drugs are
highly efficacious, and may have advantages in inflammatory conditions causing resistance to conventional ESA therapy, but con-
cerns exist regarding their safety, particularly in the longer term. This article reviews the current standards of treatment, as well as
recent novel developments in the management of anaemia in CKD.
Keywords: anaemia, erythropoietin, HIF prolyl hydroxylase inhibitors, hypoxia-inducible factor, iron
‘In a nutshell’
1. The balance between erythropoiesis-stimulating agents (ESAs) and iron supplementation has changed over the last few years,
with less emphasis on ESAs and more on iron.
2. ESA therapy and a higher haemoglobin can exacerbate a number of adverse secondary outcomes, such as stroke and venous
thromboembolism.
3. In contrast, liberal amounts of iron replacement, such as the doses used in the high-dose arm of the PIVOTAL trial—400 mg
of intravenous iron sucrose per month with safety cut-offs of ferritin (700 μg/L) and transferrin saturation (40%)—would
appear to improve a number of cardiovascular outcomes in dialysis patients, e.g. hospitalization for heart failure and possibly
myocardial infarction.
4. Hypoxia-inducible factor–prolyl hydroxylase inhibitors (HIF-PHIs) have recently been introduced as highly effective agents
for the treatment of chronic kidney disease anaemia.
5. HIF-PHIs are orally active, and allow exposure to lower circulating levels of erythropoietin, but concerns exist regarding
upregulation of other HIF-sensitive genes such as vascular endothelial growth factor, with the potential to enhance tumour
production and growth, as well as to worsen diabetic proliferative retinopathy.
INTRODUCTION but start to decline once the glomerular filtration rate (GFR) falls
below 60 mL/min, and anaemia becomes highly prevalent in pa-
Patients with chronic kidney disease (CKD) almost invariably de- tients with a GFR below 30 mL/min. The vast majority of patients
velop a progressive and debilitating anaemia which, if untreated, on dialysis require treatment for anaemia, with a few notable
usually culminates in a dependence on red cell transfusions. exceptions, e.g. when the cause of end-stage renal failure is poly-
Data from the National Health and Nutrition Examination Survey cystic kidney disease, since the cysts produce higher levels of ery-
(NHANES) in the USA [1] suggest that haemoglobin concentra- thropoietin compared with other causes of renal failure [2]. In
tions are generally well preserved in early renal insufficiency,
Received: July 28, 2023; Editorial decision: November 1, 2023
© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.
All rights reserved. For permissions, please e-mail: journals.permissions@oup.com
, I.C. Macdougall | 771
Inflammation: CRP/IL-6
Blood loss: Endoscopy/colonoscopy
Exclude other causes
1 Haemolysis: Coombs test/bilirubin/LDH/haptoglobin levels
of anaemia
Haematological disorder: Bone marrow
Ferritin
TSAT Iron supplementation
2 ? Iron deficiency
Downloaded from https://academic.oup.com/ndt/article/39/5/770/7452913 by guest on 25 May 2024
(%HRC)
(CHr)
Epoetin: IV or SC, 2000–3000 units × 2–3 per week
Darbepoetin alfa: IV or SC, 30 µg × 1 per week or 60 µg every 2 weeks
3 ESA therapy
Pegylated epoetin beta: IV or SC, 60 µg every 2 weeks or 120 µg every 4 weeks
HIF-PHIs: Oral, variable dose depending on HIF-PHI (see Table 1)
Figure 1: Stepwise algorithm depicting current standard-of-care treatment for CKD anaemia. CRP, C-reactive protein; IL-6, interleukin-6; LDH, lactate
dehydrogenase; PTH, parathyroid hormone; Hb, haemoglobin; %HRC, percentage of hypochromic red cells; CHr, reticulocyte haemoglobin content;
ESA, erythropoiesis-stimulating agent; HIF-PHIs, hypoxia-inducible factor-prolyl hydroxylase inhibitors; IV, intravenous; SC, subcutaneous.
contrast, patients with diabetes as the cause of their CKD are often Exclusion of other causes of anaemia
more anaemic for any given level of GFR compared with their non- Before embarking on treatment with iron or ESA therapy, it is
diabetic counterparts [3]. As a practical point, if a patient’s GFR is important to exclude other contributory causes of anaemia,
>60 mL/min then it is less likely that their anaemia is solely due to particularly those that are correctable, such as haematinic defi-
erythropoietin deficiency and other causes should be sought (see ciencies (iron, vitamin B12 or folate), hypothyroidism, haemolysis,
below). blood loss, primary bone marrow disorders and other haemato-
Until the late 1980s when first-generation ESAs became avail- logical conditions (such as myeloma, myelodysplastic syndrome,
able, it was commonplace for patients on dialysis to have etc.) [4]. To this end, a number of simple screening blood tests
haemoglobin concentrations of 5 or 6 g/dL and to require regu- may be helpful.
lar blood transfusions to avoid life-threatening complications of
the severe anaemia. This, however, resulted in transfusional iron Red cell indices
overload, in addition to sensitizing potential renal transplant re- When the complete (or full) blood count is requested, the
cipients to HLA antigens, thus rendering subsequent transplanta- three major laboratory parameters that are reported are the
tion more problematic. There were also potential problems with haemoglobin concentration, the white cell count and the platelet
transfusion reactions and transmission of infectious agents, par- count. However, modern day analysers provide accurate informa-
ticularly viral. tion on red cell morphology, notably the reticulocyte count, red
Modern day management of CKD anaemia seeks to avoid these cell size [mean cell volume (MCV)] and degree of haemoglobiniza-
life-threatening complications, and the vast majority of patients tion [mean cell haemoglobin (MCH), mean cell haemoglobin con-
can be effectively treated. The current standards of treatment centration (MCHC)], reticulocyte haemoglobin content (CHr), red
and novel developments in the management of anaemia will be cell distribution width (RDW) and percentage of hypochromic red
discussed below. cells (%hypoRBC). Each of these parameters can provide useful
screening information for a number of conditions.
TREATMENT STANDARDS Reticulocyte count and indices
The current management of CKD anaemia best incorporates a hi- The normal absolute reticulocyte count is somewhere be-
erarchical stepwise approach involving three distinct strategies tween 50 and 100 × 109 /L to maintain a normal haemoglobin
(Fig. 1; Table 1). concentration. Reticulocyte counts <50 indicate low marrow
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