Anaemia: iron comes first

Anaemia is common in people with chronic kidney disease (CKD). Effective treatment with iron and, if needed, erythropoietin (EPO) improves symptoms, quality of life and physical functioning in people with CKD.

In anaemia there are fewer than normal red blood cells, which carry oxygen around the body in a protein called haemoglobin (Hb). This means that less oxygen is carried to the body’s organs including the heart, the brain and muscles, and they do not function as well as they should.

Iron is key to the development and treatment of anaemia of CKD (also known as renal anaemia).

This is because, as kidney function gets worse, less iron becomes available to supply the bone marrow, where red blood cells are made after stimulation by erythropoietin (EPO). A hormone produced mainly by the kidneys, EPO is released into the bloodstream and travels to the bone marrow where it stimulates the stem cells to become red blood cells.

What causes anaemia of CKD?

Anaemia starts to develop when kidney function is less than 60% of normal, and worsens as function falls. This is why guidelines advise doctors to routinely check Hb levels at least once a year in CKD stage 3 (30-59%) and at least twice a year in CKD stage 4 (15- 29%) and stage 5 (less than 15%).

According to Professor Sunil Bhandari: “Poor absorption is one of the most important mechanisms for iron deficiency in CKD, but you lose additional iron if doctors take excessive blood tests, and if you are on haemodialysis (HD) you will lose blood during treatment. In addition, some medications commonly prescribed to kidney patients, such as ACE inhibitors (-pril drugs) and angiotensin receptor blockers (ARBs; -sartans), cause anaemia by reducing EPO production.” Sunil is a Consultant Nephrologist and Clinical Professor, Hull University Teaching Hospitals NHS Trust.

It is also possible for kidney patients to be iron deficient due to non-renal causes.

Women may be iron deficient because of heavy periods or lack of dietary iron in pregnancy.

Possible causes in both women and men include bleeding from the gut due to non-steroidal anti-inflammatory drugs, stomach ulcers or, very rarely, cancer of the bowel or stomach.

How is anaemia of CKD diagnosed?

Anaemia in people with CKD is defined as Hb less than 110 g/L.

The condition has a wide range of symptoms, but it can be overlooked by GPs and other non-specialists. Sunil explains: “The problem is that kidney patients do not present with the classic symptoms of anaemia alone. Shortness of breath is not just a symptom of anaemia; it is also a symptom of acidosis and fluid retention, which both occur in CKD. However, if a kidney patient is tired all the time, is short of breath, and looks pale, they need a blood test to check the Hb level.

“If Hb is less than 110 g/dl, we test blood levels of ferritin (a measure of stored iron) and transferrin saturation (TSAT), which checks how much iron is binding in the blood and is available. A serum ferritin of less than 100 mcg/L and/or TSAT of less than 20% indicate iron deficiency. We also check blood levels of vitamin B12 and folate, which are important for producing red blood cells. If kidney patients cannot eat well, they can become malnourished and develop vitamin deficiencies. They may also not be able to absorb vitamins effectively,” he adds.

Symptoms associated with anaemia of chronic kidney disease

  • Weakness
  • Fatigue, or feeling tired all the time
  • Headaches
  • Problems with concentration
  • Disturbed sleep
  • Paler-than-usual skin
  • Itching
  • Dizziness
  • Shortness of breath
  • Chest pain
  • Rapid heartbeat
  • Feeling cold
  • Feeling depressed

How is anaemia of CKD treated?

Vitamin B12 or folate levels can be improved with supplements, given either as tablets or injections in the case of vitamin B12.

Otherwise, treatment of anaemia of CKD involves iron supplementation, plus ESA (erythropoiesis stimulating agent) injections if needed to replace EPO.

Although a diet high in iron is conventionally advised to improve iron deficiency, it is not as effective in CKD as in the general population. People with CKD cannot absorb enough dietary iron from the gut, especially as intake of iron-rich foods may be limited by dietary restrictions in people with late-stage CKD.

How is iron treatment given?

Oral iron (tablets)

Some guidelines recommend a trial of oral iron for people with CKD who do not need dialysis or who are on peritoneal dialysis (PD). However, high doses are needed to ensure enough iron is absorbed, and the tablets may be difficult to tolerate.

“In my experience, patients do not like the side effects of oral iron like black stools, diarrhoea or constipation. Oral iron needs to be taken on an empty stomach (30 minutes before eating or at least two hours after eating) for the best chance of absorption, which increases side effects. Iron also will not be absorbed if taken at the same time as medications that act on the gut such as phosphate binders, proton pump inhibitors or ranitidine,” comments Sunil

High-dose iron infusion (intravenous)

In contrast, high-dose iron given through an infusion into a vein (intravenously) bypasses the gut. It is absorbed straight into the bloodstream and rapidly increases iron levels in the blood.

Intravenous iron is generally well tolerated. The most common side effects include a metallic taste in the mouth, feeling sick, headache and dizziness. Sometimes the infusion temporarily increases heart rate and blood pressure, but reducing the speed of the infusion can correct this. Occasionally delayed effects with muscle aches and joint pains can occur up to four days after the infusion; these settle on their own.

Sunil adds: “Very rarely, an iron infusion may cause an anaphylactic reaction. With modern irons, this risk is very low and certainly not as high as it is with, say, penicillin, but we still need to be vigilant and monitor patients carefully when they receive their iron infusion. This is why you are observed for 30 minutes after the infusion.”

Guidelines used to advise giving intravenous iron reactively when iron levels became too low. However, the randomised controlled PIVOTAL trial shows that in HD patients, compared with reactive treatment, proactive infusions to increase iron levels result in a lower risk of death, hospitalisation for heart failure and other major cardiovascular events. Proactive treatment also reduces the dose of ESA and the need for blood transfusions.

“In response to PIVOTAL, the Renal Association recently updated its anaemia guidelines, and revised guidelines are likely from NICE (National Institute for Health and Care Excellence). However, few units appear to have changed practice even though 50 HD units from the UK were involved in PIVOTAL. It is disappointing to see such inertia in response to good data from a landmark UK trial,” comments Sunil.

What about ESAs?

Guidelines do not recommend treatment with ESA unless anaemia persists after optimising iron levels.

When using ESA in CKD, Hb targets are 100-120 g/L. These target levels are lower than recommended Hb levels in healthy people (13.5-17.5 g/dL in men and 12.0-15.5 g/dL in women). This is because large studies in the United States in dialysis patients with heart disease and diabetic patients with CKD suggested that using ESAs to raise Hb above 130 g/dL increases cardiovascular risk, including the risk of stroke.

“In these studies patients were given high doses of ESA, but not enough iron in many cases. The result was very wide swings in ESA doses used, which may have been one possible cause of the negative effects. In contrast, there is increasing and reassuring safety data when using intravenous iron alone to raise Hb levels— indeed PIVOTAL showed this reduces cardiovascular risk in dialysis patients,” says Sunil.

Lack of response to ESA may be resolved by switching from a short-acting to a long-acting formulation. It is also essential to check for underlying causes for lack of response, including hyperparathyroidism, a blood disease like myeloma, or chronic infection. It is possible to develop antibodies to EPO, but this is extremely rare. “Sometimes we do not find out why a patient does not respond to ESA and we must consider blood transfusion, but this is a last resort. We want to avoid the risk of developing antibodies in someone who wants to have a transplant in the future. Blood transfusion has other risks like infection and reactions to the blood, and blood can be in short supply, especially when there are fewer donations because of Covid-19,” adds Sunil.

Anaemia of CKD: regular testing and treatment is needed

The best treatment for anaemia of CKD is a successful kidney transplant, since it restores the body’s healthy physical functioning. However, people still have CKD after a transplant and, depending on the level of kidney function, some may need treatment with iron and ESA as needed.

“It is essential for doctors to follow guidelines and check Hb regularly in people with CKD stages 3-5. Anaemia develops slowly, so kidney patients adapt and may not realise how ill they felt before their anaemia is treated. PIVOTAL has also shown that proactive iron infusion reduces cardiovascular risk and reduces the dose of ESA in dialysis patients. In future, novel drugs that help the body produce its own EPO may further improve outcomes in anaemia of CKD,” concludes Sunil.

This article by medical writer and editor Sue Lyon first appeared in the Spring 2021 issue of Kidney Matters magazine.