Anaemia of Renal Insufficiency


Richard Bright discovered the relationship of renal failure and anaemia in 1836. Anaemia of renal insufficiency is mainly results from decreased erythropoietin production and impaired supply of iron to erythroid precursors. Anaemia results in fatigue, cognitive dysfunction and cardiovascular consequences and increased cardiovascular mortality. Correction of anaemia decreases LVH, LVH related hospitalizations and mortality of cardiovascular disease. Without erythropoietin supplementation only 2% (Int J Artif Organs 1981; 4:277-9) needing haemodialysis have a hematocrit of >0.4. Availability of erythropoietin and the use of parental iron has reduced the prevalence of anaemia in patients with renal failure.

Pathogenesis of Anaemia of Renal Insufficiency

Anaemia associated with renal insufficiency results from decreased erythropoietin and iron availability.

Erythropoietin, produced by the kidney, is essential for erythropoiesis (see Erythropoietin and Erythropoietin Receptor Signalling). Renal insufficiency results in decreased renal mass and consequently in decreased erythropoietin production. Erythropoietin levels in patients with renal failure are normal or slightly elevated, but they are 10-100 times lower than a normal individuals with similar levels of anaemia. Decreased erythropoietin hampers erythropoiesis contributing to anaemia (no 1 in figure 1). Erythropoietin supplementation corrects anaemia in most but not all patients.

Three other causes of anaemia have been identified in patients with renal insufficiency. These are

  1. Impaired supply of iron
  2. Folate deficiency due to losses in dialysis
  3. Aluminium intoxication resulting in microcytic hypochromic anaemia

Folate deficiency and aluminium intoxication are of historical importance. Current management of dialysis patients includes folate supplementation and measures to prevent aluminium intoxication. Impaired iron supply to erythroid precursors remains the main cause of anaemia that does not respond to erythropoietin.

Iron is a component of heme (see heme synthesis). Patients with renal insufficiency have decreased iron availability from blood loss, impaired iron absorption and inability to use body iron stores (functional iron deficiency)

Causes of blood loss in patients with renal failure include (2 in figure 1)

  1. Gastrointestinal blood loss due to uraemia induced platelet dysfunction
  2. Blood loss due to dialysis
  3. Iatrogenic blood loss due to investigations (Transfus Med 2009; 19;309-14)

Iron supply to the erythroid precursors is also limited by impaired absorption (3 in figure 1) and a functional iron deficiency (4 in figure 1). Hepcidin plays a central role disrupting iron supply in patients of renal insufficiency. It reduces iron absorption in the gut and hampers the release of macrophage iron. The latter results in a phenomena called as functional iron deficiency i.e. diminished iron availability despite adequate iron stores. Hepcidin levels are increased from increased production because of inflammation and decreased elimination as a result of falling GFR. Infections, exposure of leucocytosis to foreign surfaces during dialysis and from the underlying cause of renal insufficiency are the sources of inflammation.

Clinical Features

The degree of anaemia co-relates with the degree of impairment of renal failure. Anaemia is rarely observed in patients with creatine clearance of greater than 45ml/1.72m2. This corresponds to a serum creatinine of 2-2.5mg/dL.  The anaemia is mild to moderate with the haematoctit stabilizing between 15-30%. Anaemia is less severe in polycystic kidney disease and to a lesser extent in hypertension. It may be more severe in diabetics. The presence of severe anaemia is an indication for evaluation for another cause of anaemia.

Signs and symptoms are those of anaemia and the underlying disease causing renal failure.

Diagnosis

A complete haemogram should be performed in all patients with chronic renal insufficiency at diagnosis. The diagnosis is made by the presence of a mild to moderate normochromic normocytic anaemia, presence of renal insufficiency and the absence of other causes of anaemia. Macrocytosis may be seen. The investigations that are usually performed in a patients with suspected anaemia of renal insufficiency include

  1. Complete haemogram with erythrocytes indices to determine severity of anaemia and to exclude co-existing diseases like iron deficiency and aluminium intoxication (microcytosis) or Folic acid/vitamin B12 deficiency (macrocytosis).
  2. The reticulocyte counts are normal but may rise with azotaemia
  3. Serum iron, total iron-binding capacity, percent transferrin saturation and serum ferritin need to be performed to asses the iron stores and iron delivery

Despite the fact that there is a relatively deficiency of erythropoietin, erythropoietin levels are not useful in the diagnosis of anaemia of renal insufficiency. The bone marrow tends to be moderately hypercellular with a slight erythroid hyperplasia.  A bone marrow aspiration is not necessary for diagnosis.

Treatment

The treatment of anaemia of renal insufficiency in transplant ineligible patients consists of erythropoiesis stimulating agent (ESA), iron and blood transfusion. Transplant when indicated cures anaemia in 80% of the patients. Most authorities define anaemia as a haemoglobin of 13-13.5g/dL in men and less than 12g/dL in women.

Iron therapy

All patients with chronic renal insufficiency need iron supplementation. The route of supplementation may be oral or intravenous. Severity of anaemia, patients preference and adherence and previous experience with that route iron therapy are few of the factors determining the choice. In a meta-analysis of oral iron vs. parental iron, parental iron raised the concentration of haemoglobin by >1g/dL more often than oral iron. The risk of hypotension was higher and gastrointestinal side effects lower with parental iron (Am J Kidney Dis. 2016 Nov;68(5):677-690). As the safety of intravenous iron preparation has increased so has their use. Many trials comparing oral with intravenous iron therapy have shown a better response with intravenous iron. However intravenous iron therapy has not been show to be superior in some trials (Clin J Am Soc Nephrol. 2016 Jul 7; 11(7)).

Erythropoiesis Stimulating Agenst (ESA)

ESA are indicated in patients who have adequate iron reserves. These are patients with transferrin saturationis >25 percent and ferritin >200 ng/mL. ESA should be used in patients with iron deficiency (actual or functional) after iron replenishment. Two ESAs available are erythropoietin and darbepoietin. Treatment with ESA results in improved quality of life, improved cognitive function and reduces left ventricular hypertrophy. The target of therapy is to increase the haemoglobin to 11-12g/dL. Higher targets are associated with more side effects. The rise is typically achieved in 6-8 weeks of therapy. Erythropoietin is administered in a dose of 100-150 units every week. Hypertession is seen in about 35% of the patients. Darbepoietin as administered in a dose 0.45 μg/kg/week for patients on dialysis.

Erythropoietin resistance is failure to respond to erythropoietin. The causes of erythropoietin resistance include inadequate iron availability (decreased reserves and/or functional iron deficiency) inadequate dialysis, marrow fibrosis associated with secondary hyperparathyroidism, folate deficiency, aluminium intoxication and co-existing inflammation. Dialysis should reduce blood urea to less than 35% to allow for optimal erythropoietin action.

 

Renal replacement therapy

Renal Allograft: Renal allograft is effective correction of anaemia in 80% of the patients. The rise is seen in 8-10 weeks. About 20% of the patients may get post-transplant erythrocytosis. The causes of failure of haemoglobin to rise after transplant include hemorrhage, intense immunosuppression or graft rejection

Dialysis: Dialysis has a small effect on the anaemia presumably by clearance of inhibitors. Peritoneal dialysis (PD) is more effective than haemodialysis. Reason a higher efficacy of PD is more effective in unknown but more effective removal of middle molecules (500-1500kD) and lesser of inflammation compared to HD may explain the higher haemoglobin in patients with on PD.

 

 

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Oral Iron Therapy


Iron deficiency anaemia is treated by iron supplementation that may be administered orally or parenterally.  Oral iron absorption is inefficient, is interfered by food and is associated with high incidence of gastrointestinal adverse effects. About 17% of the world population is estimated to be suffering from iron deficiency. Iron deficiency is more common the poorer regions of the world. These regions have limited resources allocated for healthcare. Oral iron is inexpensive and convenient to administer making it the modality of choice for initiation of treatment of iron deficiency. The availability of safer parenteral iron preparations that can replete the iron deficit in one dose has reduced the threshold of switching a person intolerant to iron to parenteral iron.

Oral Iron Absorption

Dietary iron may be heme iron or non-heme iron. Heme iron is absorbed after oxidation to hematin. The absorption of heme iron is more efficient. Dietary non-heme iron is present in the ferric state. Ferric iron is insoluble and needs to be reduced to ferrous iron. Gastric acidity aids this conversion. Medicinal iron is most often administered in the ferrous state. Ferrous iron tends to oxidize to ferric iron at physiological pH. Gastric acid lowers the pH and retards oxidation. The absorption of non-heme iron is aided by ascorbate, animal proteins, human milk, keto sugars, organics, amino acids that form soluble chelates and retarded by phytates present in grains and vegetables, dietary fibre, polyphemols present in tea, coffee and wine, phosphates and phosphoproteins present in egg yolk, bovine milk, calcium and zinc. For a detailed discussion on iron absorption see intestinal iron absorption. Preparations containing iron in the ferric state have a 3-4 fold lower bioavailability than ferrous iron preparations. Ferric iron is insoluble in the alkaline medium of the duodenum and needs to be converted to ferrous iron (ScientificWorldJournal. 2012; 2012: 846824).

Oral Iron Preperations

Oral iron preparations may be heme or non-heme. Heme iron is available as heme iron polymer. Non-heme iron may be in the ferrous or ferric form. Carbonyl is pure iron prepared from the decomposition of iron pentacarbonyl. The preparations are listed in the table below.

 

Preparations Iron Content
Ferrous Sulfate, anhydrous 30%
Ferrous Fumarate 33%
Ferrous Sulfate 20%
Ferrous carbonate, anhydrous 48%
Ferrous Gluconate 12%
Ferric Ammonium Citrate 18%
Ferric bisglycinate 20%
Ferric pyrophosphate 12%
Carbonyl iron ~100%
Heme-iron peptide 100%
Polysaccharide iron complex 100%

Indications of Oral Iron Therapy

Oral iron is indicated for prevention and treatment of iron deficiency anaemia. The rate of iron delivery is insufficient to provide iron when erythropoiesis is stimulated by erythrocyte stimulating agents like erythropoietin and darbepoetin. Oral iron should not be used for such patients.

Trial of Oral Iron Therapy

Serum ferritin is an indicator of total body iron. It is also an acute phase reactant. Low ferritin indicates iron deficiency. The traditional cutoff is 12ng/mL. At this cutoff the sensitivity of ferritin for the diagnosis of iron deficiency anaemia is only 25%. The sensitivity can be increased to 92% with a positive predictive value of 83% if a cutoff of 30ng/mL is used. A trial of oral iron may be given if other causes of anaemia are excluded.

Contraindications to Oral Iron Therapy

  1. Primary hemachromatosis: Primary hemochromatosis is a is absolute contraindication
  2. Peptic ulcer, regional enteritis, or ulcerative colitis can be exacerbated by oral iron.
  3. β-Thalassaemia trait is a relative contraindication. Some patients may develop iron overload. Patients should be given iron only if iron deficiency is established by laboratory investigation.

Failure of Oral Iron Therapy

  1. Failure to take prescribed medication: Oral iron therapy causes gastrointestinal adverse effects in a large proportion patients that are severe enough in some to discontinue therapy. A detailed history must be taken to ascertain that the patient has taken the prescribed dose.
  2. Incorrect or incomplete diagnosis: Iron deficiency anaemia is hypochromic microcytic (see Evaluating Anaemia). Other diseases that result in hypochromic microcytic anaemia are thalassaemia and anaemia of chronic disease. Both are common and can both be confused with iron deficiency as well as co-exist with iron deficiency. Thalassemia trait affects about 1.5% of the world population. About 1.4% of the population is estimated to have anaemia due to infection, inflammation or chronic renal disease (https://dx.doi.org/10.1016%2FS0140-6736(15)60692-4). Incidental occurrence of iron deficiency with thalassaemia trait or anaemia of chronic disease will result in an incomplete response to iron supplementation. Some inflammatory conditions e.g. ulcerative colitis cause blood loss. Blood loss may be seen due to use of non-steroidal inflammatory agents in patients with autoimmune arthritis. Anaemia in these patients shows an incomplete response to iron supplementation because part of the anaemia results from chronic inflammation.
  3. Insufficient amount or inappropriately taken oral iron: The ideal dose is 200mg of elemental iron taken 2 hours before or 1 hour after food. Food interferes with iron absorption but also relieves gastrointestinal adverse effects. Gastrointestinal adverse effects are related to dose. Prescriptions of oral iron may have an insufficient dose or may be administered after food to reduce gastrointestinal adverse effects. This results in an inappropriate haemoglobin response.
  4. Iron demand exceeding intake: Iron demand may exceed supply if there is continued blood loss or in patients where erythropoiesis is stimulated with an erythropoiesis stimulating agent like erythropoietin or darbepoietin. In both these situations the rate of oral iron absorption limits iron availability. These patients need intravenous iron.
  5. Malabsorption of iron: Food interferes with oral iron absorption. Ferrous iron is rapidly oxidised to ferric iron at physiological pH. Gastric acid reduces ferric iron to ferrous iron. Proton pump inhibitors, H2 antagonists, antacids and gastrectomy reduce acidity and can interfere with iron absorption. Iron malabsorption may be seen as part of a malabsorption syndrome. Iron deficiency refractory to iron is rare. Iron refractory iron deficiency anaemia is a disorder resulting from mutations in the TMPRSS6. This mutations results in increase hepcidin production which is sensed by the body as an iron repeated state. Iron is not absorbed despite iron deficiency. The patients do not respond to oral iron and shows a partial response to parenteral iron.

 Interactions

  1. Interaction of iron with food: The absorption of non-heme iron is affected by food (See Intestinal Iron Absorption).
    1. Foods enhancing iron absorption: Ascorbate, animal proteins, human milk, keto sugars, organics, amino acids that form soluble chelates with iron enhance absorption of non-heme iron.
    2. Inhibiting iron absorption: `Inhibitors of absorption of non-heme iron include
      1. Phytates present in grains and vegetables
      2. Dietary fibre
      3. Polypohenols present in tea, coffee and wine,
      4. Phosphates and phosphoproteins present in egg yolk, bovine milk
      5. Calcium and zinc.
  2. Drug-Iron interactions
    1. Iron decreases the absorption of ACE inhibitors, bisphosphonates, levodopa, levothyroxine, penicillamine, quinolone and tetracyclines
    2. The absorption of iron is decreased by drugs that reduce gastric pH. These include H2 antagonists(Cimetidine, ranitidine, famotidine), proton pump inhibitors (omeprazole, pantoprqzole, esomeprazole, lansoprazole, rabeprazole, etc), antacids and cholesterol lowering agents (Cholestyramine and Colestipol).

Dose

  1. Children: 3–6 mg/kg daily in 3 divided doses.
  2. Adult: Usual therapeutic dosage: 50–100 mg 3 times daily but a dose of 200mg produces the maximal results. A smaller dosages (e.g. 60–120 mg daily) may be given if patients are intolerant of oral iron, but response in such patients takes a longer time.

Side Effects Of Oral Iron

  1. Gastrointestinal: The commonest adverse effects of iron are gastrointestinal symptoms, including heartburn, nausea, abdominal cramps, diarrhoea or constipation. These may be seen in up to a fifth of the patients. They can be reduced by decreasing the dose or taking iron after food. Taking iron with food can reduce the absorption by about 50%. Enteric coated preparation decrease the side effects by delaying the release of iron. Delaying release may bypass the duodenum that is the site of absorption of iron. The decrease in absorption is particularly marked in patients with aclorhydria as they can not dissolve the enteric coating. The stool of patients taking iron supplements may be discoloured black or green.
  2. Discolouration of teeth: Iron syrups may cause staining to teeth.
  3. Iron overload: Iron overload from oral iron therapy is rare. It has been described in patients with hemachromatosis and chronic haemolytic anaemias.
  4. Iron Poisoning: Iron poisoning usually occurs in children, particularly those younger than 5 years of age, because of accidental ingestion of medicinal iron. Children are likely to ingest these believing them to be candies.

Intravenous Iron


Iron deficiency, the commonest cause of anaemia, is treated by iron supplementation. Oral iron, introduced by the French physician Pierre Blaud in the 19th century is the mainstay of therapy of iron deficiency. Oral iron is inexpensive and safe but is poorly absorbed and causes abdominal adverse effects in 35-59% of the patients. Injectable iron preparations were initially developed for the treatment of iron deficiency in patients intolerant to iron. Their use became more prevalent when it became clear that iron deficiency was a common cause of failure of erythropoiesis stimulating agent therapy and that oral iron was insufficient for this indication. The acceptance of intravenous iron was accelerate by the improved safety profile of the recently introduced parental iron preparation. The threshold for opting for intravenous iron is much lower than it was about two decades ago.

Is it possible to inject an iron salt, say ferric chloride, for iron deficiency, like it is to inject calcium chloride for hypocalcaemia? Iron, unlike calcium or potassium,  produces free radicals (oxyradicals) that can damage macromolecules and result in cellular injury. Ferric hydroxide,  the first injectable iron preparation used, caused an immediate release of iron in circulation resulting in severe reactions.  When an iron oxide, hydroxide or an iron salt is used, only a small dose can be safely administered. One estimate calculated the maximum iron permissible as 8mg/day (this is equivalent of the unbound iron binding capacity of transferrin). It would take about 6 months to bring up haemoglobin at this dose.

About  25mg of iron is delivered each day to the erythroid precursors for haemoglobin synthesis. Iron is a poorly absorbed micronutrient and stores are needed to  provide for sudden increase in demand as may be seen in patients with acute blood loss. Given the propensity of iron to cause free radical induced cellular injury, transport and storage systems capable of protecting the body from iron have evolved. Iron is transported bound to transferrin and stored as ferritin and haemosidin. In both the situations iron is bound to apoproteins (apotrasferrin and apoferritin) and this binding does not allow free radical generation.

Erythrocyte destruction takes place in the macrophages and macrophages have systems for the handling, storage and recycling of iron. Injectable iron preparations have a carbohydrate shell that prevents exposure of the plasma to free iron.  Injectable iron preparations are taken up by macrophages of the reticuloendothelial system by endocytosis. The iron is released and enters the macrophages iron pool. This iron has a fate similar to iron reaching the macrophage from other sources viz. intestinal absorption and erythrocyte destruction. Binding iron to carbohydrate shell has made it possible to administer as high as dose as 1000mg over as short a time as 15 minutes. This is a 125 fold increase over the amount of iron that can be administered without the carbohydrate shell.

Injectable iron preparations share a common structure. They have a core of iron oxide/hydroxide that is associated with a carbohydrate shell. The carbohydrate shell  keeps free iron from entering the plasma and in a way performs the same function as transferrin. The antigenicity of the shell and the strength of binding between the iron core and the carbohydrate shell determines the side effects and the maximum dose per injection.

Preparations of Injectable Iron

The preperations of injectable iron include

  1. Preparations with a strong association between iron core and the carbohydrate shell
    1. High-Molecular weight iron dextran
    2. Low -molecular weight iron dextran
    3. Ferric carboxymaltose
    4. Ferumoxytol
  2. Perperations with a weak association between iron core and carbohydrate shell
    1. Iron Sucrose
  3. Preperations that have a labile low molecular weight components
    1. Ferric Gluconate
    2. Iron-Sorbitol-Citric Acid Complex, Dextrin-Stabilized
Table 1 – parentral iron preparations
Drug Shell MW T1/2 Labile
Iron
Maximum
Dose and administration
HMW ID High moleculer weight dextran 265 60 1-2% Should be administered 1 hr after an intravenous test dose (0.5ml over at least 5 minutes) Maximum dose 20mg/kg. Administered as intravenous bolus 100mg/day slowly. A total dose infusion may be given over a prolonged period.
LMW ID  Low molecular weight dextan  165  20  1-2% Should be administered 1 hr after an intravenous test dose (0.5ml over at least 30 seconds). It may be administered as daily iv bolus of 100mg over 2 mins or a a total dose infusion over 3-4 hours may be administered 20mg/kg
Iron Sucrose  Sucrose 30-60  6  4-5% up to 300mg in a single dose, higher doses have been administered over as a prolonged infusion. May be administered undiluted as an iv bolus 200mg over at least 10 mins or as an infusion in 0.9% saline over 15-60 minutes
Ferric Gluconate  Gluconate  289-440  1  5-6% 125mg, iv bolus at 12.5mg/min or as a 1 hr infusion in 0.9% saline
Ferric Carboxy-maltose Carboxy-maltose  150  16  1-2% The maximum dose is 20mg/kg (max 1000mg). Doses of 200-500mg should be administered at 100mg/min, doses between 500mg and 1000mg should be administered over 15 minutes. It may be administered as an iv infusion diluted in 0.9% saline
Ferric Isomaltoside Isomaltoside 150  20  <1% May be administered as an intravenous bolus dose of 500mg un to three times a week at the rate of 50mg/min or 20mg/kg (maximum 1000mg) in 0.9% saline over 1 hour
Ferumoxytol Carboxy-methyl Dextran 750 15 <1% 510mg as a iv bolus at the rate of 30mg/sec. A second dose may be administered after 3-8 days

The parental iron preparations differ in the carbohydrate that surrounds the iron core. The therapeutic implications of these differences are:

  1. Antigenicity: Dextran is antigenic. Patinets may have performed antibodies to dextran or may develop antibodies during therapy. All iron preparations  containing dextran can give rise to anaphylaxis. The risk is greatest with high molecular weight iron dextran. Anaphylaxis may also be seen with low molecular weight iron dextran though the risk is lower and has also been reported with ferumoxytol that contains carboxymethyl dextran.
  2. Maximum dose per injection: All intravenous iron preparations tend to release labile iron. There is an inverse relationship between the amount of labile iron released and the strength of association between the iron core and carbohydrate shell. Higher the molecular weight of the iron preparation, stronger is the association. Labile iron is taken up by transferrin. Non-transferrin bound iron (NTBI) appears when the binding capacity of transferrin is overwhelmed. NTBI is responsible for tissue damage and restricts the dose of a injectable preparation that can be given in a single infusion. Iron preparations may be classified on the basis of strength of the associations between iron core and the carbohydrate shell. Iron dextran, ferric carboxymaltose and ferumoxytol, that have a high molecular weights have a tight binding between iron core and the carbohydrate shell, release up to 2% labile iron. These can be given in a large single dose and are suitable for total dose infusion. Iron sucrose has a weaker association between iron core and carbohydrate shell and has 4-5% labile iron. This limits the amount of drug that can be administered at one time to 300mg. Ferric gluconate is a large molecule but has two types of polymers. Lower weight polymers (about 18,000) have a weaker association between iron and carbohydrate limiting the dose to 125mg per dose.

Dose and Administration

The total dose of parenteral iron is calculated as follows

Total iron dose (mg) = weight (kg) X Hemoglobin deficit  X 0.24 + 500

Haemoglobin deficit (g/L) = Target Haemoglobin (g/L) – Actual Haemoglobin (g/L)

Adverse Effects

  1. Infusion Related Events: the risk of infusion related events (per million) is 0.6 for iron sucrose, 0.9 for ferric gluconate, 3.3 for low molecular weight dextran iron and 11.3 for high molecular weight iron dextran.  Iron sucrose has been safely administered to patients who having sensitivity to iron dextran.  Despite the fact that some studies suggest that low molecular weight iron dextran in as safe as iron sucrose, a test dose must be administered before any iron dextran preparation.
  2. Delayed Reactions to Intravenous Iron: A syndrome charecterized by fever, arthralgia and lymphadenopathy may be seen as a delayed consequence of intravenous iron therapy. Premedication with steroids may reduce the risk of this manifestation.

Further Reading

  1. Rodolfo Delfini Cançado, Manuel Muñoz. Intarvenous iron therapy: How far have we come? Rev Bras Hematol Hemoter. 2011; 33(6): 461–469.
  2. Hayat A. Safety Issues With Intravenous Iron Products in the Management of Anemia in Chronic Kidney Disease. Clin Med Res. Dec 2008; 6(3-4): 93–102.
  3. Peter Geisser and Susanna Burckhardt The Pharmacokinetics and Pharmacodynamics of Iron Preparations. Pharmaceutics. Mar 2011; 3(1): 12–33.