Why anemia in chronic kidney disease

They also promote the uptake of iron bound to transferrin into macrophages, via the transferrin receptor Moreover, hepcidin is eliminated by kidney and its clearance is reduced as eGFR declines. All these mechanisms favor intracellular iron storage, limiting the availability of iron in CKD.

Anemia management in CKD has evolved dramatically: from the first oral iron supplements introduced in s ferrous sulfate , the use of red blood cell transfusions along the XX century, the appearance of the first rhuEPO use in late s followed by long-acting ESAs, to finally, the widespread use of intravenous iron supplements in recent years.

However, the actual management of anemia in patients with CKD varies among different countries and medical units 60 , Some controversies exist about the optimal Hb and iron targets.

Table 1 summarizes the main differences. Table 1. Summary of the key recommendations of the most recent anemia guidelines. Further, these guidelines do not include more recent studies assessing the efficacy and safety of IV iron, as well as different strategies of iron repletion, which will probably change the clinical practice in the future. In addition, a high-dose low frequency administration strategy in dialysis dependent chronic kidney disease DD-CKD patents is safe and improves outcomes in patients It is produced by recombinant DNA technology in cell cultures.

Darbepoetin alfa DA and methoxy polyethylene glycol-epoetin beta where developed thereafter and presented a prolonged half-life. More recently, biosimilars of the original epoetin have been introduced in the market. Not all ESAs are equal. They have different pharmacokinetic and pharmacodynamic properties, such as different half-lives and EPO receptor affinity, allowing a less frequent dosing and ease of administration for NDD CKD patients with long-acting ESAs.

In addition, it is important to point out the fact that the conversion factor between short-acting and long-acting ESAs is likely not linear. In fact, at higher doses, long-acting ESAs are more dose-effective However, based on efficacy and safety data, various Cochrane metaanalysis advocate for insufficient evidence to suggest the superiority of any ESA formulation or any ESA administration pattern 65 , Some observational studies have shown conflicting results regarding such outcomes.

These results should be taken cautiously due to the study design and the risk of bias. The target Hb concentration during ESA therapy is still controversial.

Studies early after the appearance of rhuEPO demonstrated its efficacy in reducing the need for blood transfusions, the symptoms related to anemia and an improved quality of life 70 , Various landmark trials have dwelt on the convenience of a complete correction of anemia. The use of darbepoetin alfa did not reduce the risk of either of the two primary composite outcomes either death or a cardiovascular event or death or a renal event , and was associated with an increased risk of stroke 65 , 72 — Yet, it is still unclear whether this increased risk is due to the higher ESA doses and the possible non-erythropoietic effects, whether it is due to the underlying systemic inflammation in patients with ESA-hyporresponsiveness, rather than due to the high Hb level itself Conversely, although some trials have demonstrated significant improvements in quality of life QoL in patients targeted to normal Hb levels 73 , 75 , 77 the clinical relevance of these findings are questioned.

The results of these trials were highly influential in changing the guidelines and clinical practice of anemia in NDD-CKD. Individualizing the Hb target relative to the patient's risks, basal conditions and preferences is advisable. Guidelines acknowledge that the optimal strategy to manage iron metabolism remains unclear, and advocate for balancing the potential benefits and risks of iron supplementation 13 , 62 , In recent years some good quality pre-clinical studies, clinical trials and epidemiological studies have shed some light on the therapeutic approach regarding iron deficiency in CKD and will surely change clinical practice.

Specifically, in hemodialysis patients, oral preparations seem to be useless, maybe except for the phosphate binder ferric citrate In addition, gastrointestinal intolerance and constipation reduce tolerance and compliance of oral iron formulations However, some concerns raised about IV iron formulation such as enhanced oxidative stress, endothelial dysfunction or the potential role in favoring infection. Further, IV iron administration has been associated with an increased risk of hypotension, headaches or hypersensitivity reactions.

Labile iron, which is the iron that is freed into the circulation after administration and non-bound to transferrin, is an important cause of such adverse reactions. IV iron supplements are non-biologic complex drugs. An iron core, covered by a complex structure of polysaccharides forms them. Indeed, the differences in the structure of the molecule among different IV iron formulations may be responsible for the differences in outcomes of each IV iron formulation.

On the other hand, there is growing evidence that oral compound can have a deleterious effect on gut microbiota which may worsen uremic dysbiosis 81 , As mentioned before, iron is essential for an adequate erythropoesis.

Unfortunately, we have no evidence of the effect on hard end-points. Moreover, the risk of Hb overshooting depends on high levels of EPO but no IV iron use, since iron is not a growth factor. Further, a meta-analysis demonstrated that these benefits of IV iron therapy were independent of the presence of anemia.

In a small study in patients with HF, CKD and anemia with iron deficiency, IV iron was associated with an improvement of myocardial function and of cardiac dimensions 89 , similar to the observations in another pilot study There is a considerable correlation between heart failure, iron deficiency and renal failure and each comorbidity reduces the survival of these patients Moreover, newer IV iron formulations are more stable and have safer profiles that allows the administration of higher doses of iron per session 95 , The recent PIVOTAL trial has confirmed the efficacy and safety of high-dose IV iron sucrose: it is a UK open label, randomized controlled trial among 2, incident hemodialysis patients, that compared a proactively administered high-dose IV iron regimen with a reactively administered low-dose regimen.

The trial demonstrated that a proactive high-dose schema reduced the death of all causes or an aggregated of non-fatal cardiovascular events [HR de 0. In addition, the high-dose regimen was not associated with higher risks of death, major adverse cardiovascular events, or infection These findings should lead to a change in clinical guidelines.

Iron overload is a condition of elevated body iron content associated with signs of organ dysfunction that is presumably caused by excess iron. Some studies have demonstrated an increase in the liver iron content in hemodialysis patients, and an association between hepatic iron overload and hepatic steatosis has been recently described However, its clinical relevance is still not known, and no deposits have been observed in other territories, such as cardiac or pancreatic 99 — A metaanalysis of clinical trials and observational studies in the setting of hemodialysis suggests that patients that received higher doses of IV iron did not show a higher risk of mortality, infections or cardiovascular events Nonetheless, the strength of the findings is limited by the small number of patients and of events in the clinical trials, and by the statistical heterogeneity in the observational studies included.

These findings should be taken cautiously due to the presence of possible confounding factors. The upper limits of iron targets and the long-term safety of high doses of IV iron supplementation, specially of the accumulated high iron doses in hemodialysis patients, still needs to be clarified.

There has long been a concern whether iron supplements increased the risk of infections. A sub-analysis of PIVOTAL study did not show differences in infection episodes, hospitalization or death for infection between the proactive high dose regimen and reactive low dose-iron groups of patients In recent years, new drugs have been developed for the treatment of anemia.

These drugs inhibit the action of prolyl-hydroxylase, which leads to an increase in the levels of HIF, and therefore, to an increase in endogenous EPO All of them are administered orally.

However, they have differences in pharmacodynamics and pharmacokinetics, which probably determine differences in their interaction with the HIF system, and thus lead to differences in efficacy and safety profiles Table 2. Table 2. Pharmacological characteristics and current knowledge status of different Hypoxia-inducible factor prolyl hydroxylase inhibitors.

These studies had a relative small sample size a study population and of short duration. The former compared roxadustat with placebo, without adjuvant iron supplements, and demonstrated its efficacy in rising hemoglobin levels after 9 weeks The latter compared roxadustat with epoetin alfa, with iron supplement only as a rescue therapy.

After 26 weeks of follow up, the attained hemoglobin levels in the roxadustat group were non-inferior to those in the epoetin alfa-arm, and both groups had a similar safety profile These results were similar to those found by a phase 3 study comparing roxadustat to ESAs in hemodialysis and peritoneal dialysis patients in Japan , Interestingly, patients receiving roxadustat had reduced iron needs, and those on roxadustat and an elevated C-reactive protein were able to increase Hb levels.

Among 1. Regarding adverse events, both arms of treatment had comparable safety profiles regarding cardiovascular events and all-cause mortality This phase 3, randomized, open-label, active-controlled study evaluated the efficacy and safety of roxadustat compared to DA in the treatment of anemia in NDD- CKD patients.

The median time of follow up was weeks and the study enrolled adult anemic patients with CKD stages 3—5. Roxadustat was non-inferior to DA in the primary endpoint, which was the achievement of Hb response during the first 24 weeks of treatment.

Regarding secondary efficacy endpoints, roxadustat was superior in decreasing low-density lipoprotein cholesterol and in time to first IV iron use. Roxadustat was non-inferior in blood pressure control and time to first occurrence of hypertension, in changes in Quality of life scores, and in Hb change.

The occurrence of treatment-emergent adverse events TEAEs was similar between the two groups, and the TEAEs leading to withdrawal of treatment were more frequent in the roxadustat group. They reported no significant differences between groups in adjudicated cardiovascular events.

In all the Roxadustat studies the roxadustat patients presented an early and sustained LDL-reduction as a pleiotropic effect.

Another compound, vadadustat has also been approved in Japan in The results of two phase III trials comparing vadadustat vs. Over patients were followed for 52 weeks in each study. In both trials, vadadustat showed non-inferiority in maintaining Hb levels within the target range and a similar safety profile. Vadadustat did not meet the pre-specified non-inferiority criterion compared to DA with regards to cardiovascular safety. By the time of elaboration of the present manuscript, the Cochrane Kidney and Transplant Group.

Has published the protocol for a systematic review on HIF-PHIs for the treatment of anemia of chronic kidney disease From a mechanistic point of view, the inhibition of prolyl-hydroxylases prevents HIF from degradation, leading to an increase of endogenous EPO within the physiological range, rather than the pharmacological levels achieved by current ESAs.

However, as mentioned before, HIF also modulates many other non-erythropoietic genes. This activity would explain the potential beneficial effects seen in pre-clinical and early clinical studies such as an improved iron utilization, HDL and LDL lowering effect, ischemia protection and a protective effect on CKD progression, improved neo-vascularization or better blood pressure control Nonetheless, potential deleterious side effects due to the modulation of other genes with this new class of drugs have also been postulated, notably tumor progression, enhanced vascular calcification, enhanced growth of renal cysts, worsening of retinopathy, or an increase in pulmonary artery pressure.

In addition, whether these prolyl-hydroxylase inhibitors inhibit other di-oxygenases beyond HIF-PHIs and thus other pathways is unknown. Data from large phase III studies are still to be published and will surely help to answer these open questions.

However, more data is required regarding their long-term safety and their possible non-erythropoietic effects. In addition, the subset of patients that may benefit from these new agents still needs to be elucidated. Infection with severe acute respiratory syndrome coronavirus 2 SARS-COV-2 has become a worldwide pandemic during and millions of cases have been reported worldwide.

The coronavirus disease can lead to sepsis, acute kidney injury AKI , multiple organ dysfunction and an atypical form of the acute distress respiratory syndrome. In an observational study Among 11, patients across 13 New York hospitals admitted between March 1 and April 27 , an elevation in D-dimer level was associated with a lesser median hemoglobin level and a greater serum ferritin level. In these cases, the efficacy of ESAs is limited and they could even be potentially harmful.

Fishbane et al. Regarding iron supplementation, systemic inflammatory processes as happens with severe COVID 19 decrease the availability of iron. Furthermore, iron is also essential for viral replication In addition, patients with viral infections and iron overload have a poor prognosis. Therefore, limiting iron supplements could be beneficial for patients with severe COVID 19 although more studies are need to shed light into this subject Observational studies in NDD-CKD patients suggest that iron deficiency is associated with worse outcomes, paving the way to randomized controlled trials that demonstrate the benefit of correcting iron deficiency beyond anemia.

However, more data is required to confirm these findings. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors gratefully acknowledge the cooperation Ms.

Nephrology dialysis transplantation quality of life in dialysis patients. A Spanish multicentre study. Relationship between hemoglobin level and quality of life in anemic patients with chronic kidney disease receiving epoetin alfa. Curr Med Res Opin. Hyporesponsiveness to erythropoiesis-stimulating agents and renal survival in non-dialysis CKD patients. Nephrol Dial Transplant. Kidney function and anemia as risk factors for coronary heart disease and mortality: the atherosclerosis risk in communities ARIC study.

Am Hear J. Griffin P. Rodgers explaining the importance of participating in clinical trials. You can view a filtered list of clinical studies on anemia in CKD that are open and recruiting at www.

You can expand or narrow the list to include clinical studies from industry, universities, and individuals; however, the NIH does not review these studies and cannot ensure they are safe. Always talk with your health care professional before you participate in a clinical study. The NIDDK translates and disseminates research findings to increase knowledge and understanding about health and disease among patients, health professionals, and the public. Berns, M. How is anemia related to chronic kidney disease?

Does anemia in CKD have another name? How common is anemia in CKD? Who is more likely to have anemia in CKD? What are the complications of anemia in someone with CKD? What are the symptoms of anemia in someone with CKD? Seek care right away What causes anemia in CKD?

How do health care professionals diagnose anemia in CKD? How do health care professionals treat anemia in CKD? Can I prevent anemia in CKD? How does eating, diet, and nutrition affect anemia in CKD? Your risk for anemia increases as your kidney disease gets worse.

Symptoms of anemia in CKD may include fatigue or tiredness shortness of breath unusually pale skin weakness body aches chest pain dizziness fainting fast or irregular heartbeat headaches sleep problems trouble concentrating Fatigue can be a symptom of anemia. Talk with your health care professional if you are feeling unusually tired or have other symptoms of anemia. If you have difficulty breathing or shortness of breath, seek immediate medical care. What causes anemia in CKD?

Anemia in people with CKD often has more than one cause. Medical history Your health care professional will record your medical history and may ask about your symptoms current and past medical conditions prescription and over-the-counter medicines you take your family history Physical exam During a physical exam, your health care professional may check your blood pressure check your heart rate examine your body, including checking for changes in skin color, rashes, or bruising Blood tests Health care professionals use blood tests to check for signs of anemia or other health problems.

Blood count tests can check many parts and features of your blood, including the number of red blood cells average size of red blood cells amount of hemoglobin in your blood and in your red blood cells number of developing red blood cells, called reticulocytes, in your blood Some of these blood count tests and others may be combined in a test called a complete blood count , or CBC.

Treatments for anemia may ease your symptoms and improve your quality of life. Your blood may not have enough red blood cells to deliver oxygen to your muscles. By increasing your breathing rate, your body is trying to bring more oxygen into your body. Sensitivity to the cold may mean there is not enough oxygen being delivered in the blood to your body. Take our short quiz to learn more about the symptoms of anemia.

All of the cells in your body live for a certain amount of time and then die. Your body is always working to make new cells to replace the ones that have died. Red blood cells live for about days. Your kidneys help your body make red blood cells. Healthy kidneys make a hormone called erythropoietin EPO. EPO sends a signal to the body to make more red blood cells.

This means fewer red blood cells are available for carrying oxygen through your body, leading to anemia. Iron is a mineral found in many foods, such as meats and leafy greens. Your body uses iron to make red blood cells. A common cause of anemia in people with CKD is iron deficiency. Iron deficiency means you do not have enough iron in your body.

It can be caused by not getting enough iron in your diet or by losing blood, either through blood tests or during dialysis. Around half of people with CKD stages 2 to 5 have some kind of iron deficiency. However, there are also other types of anemia. Talk to your doctor to learn more. Talk to your doctor if you think you may have anemia.

The only way to know if you have anemia is to have a blood test. When you have kidney disease, your doctor will want you to have blood tests often. These tests are used to check not only your kidney function, but also for signs of any other problems, such as the number of red blood cells and how much iron you have in your body.

The test for anemia is a simple blood test to check for the amount of hemoglobin in your blood. Hemoglobin is a part of your red blood cells. Figuring out the amount of hemoglobin you have in your blood can tell your doctor how many red blood cells you have.

Getting your anemia treated can help you feel better. Depending on the cause of your anemia, your doctor may recommend one of the following treatments:. Doctors and researchers are working on potential new treatments for anemia. New treatments in development are tested in clinical trials. If you think you might have anemia, talk to your doctor about getting tested. Anemia and end-stage renal disease ESRD , also known as kidney failure, often go hand in hand.

Most people with kidney failure who are on dialysis have anemia. Kidney transplant patients are also at higher risk for anemia. Learn more. Talk with your doctor or another member of your health care team to find out more about your anemia symptoms and treatment options. Our Talk to Your Doctor Guide can help you get the conversation started. Note: This survey is not a medical diagnosis. This guide is an awareness tool designed for you and your doctor to use together.