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historically difficult to treat because the crux of the treatment relies on the elimination of the chronic disease and inflammation. In some cases, erythropoietic‐stimulating agents will improve haemoglobin levels, but care must be taken to diagnose and treat any concomitant iron deficiency for these agents to be effective.

      Anaemia of chronic kidney disease

      Anaemia of chronic kidney disease (CKD) is quite prevalent in older adults because of the high prevalence of CKD in the older population. In a report released by the National Kidney Foundation, 45–70% of adults over 75 meet the diagnostic criteria for CKD (i.e. glomerular filtration rate of less than 90 mL/min).⁶¹ In another study focused specifically on nursing home residents with a diagnosis of CKD, 51–60% were also found to have anaemia.⁶² Although anaemia is deleterious in any individual, it is thought to be particularly onerous in those with CKD who are receiving haemodialysis. In a large retrospective study of CKD patients on dialysis, haemoglobin levels of less than 8 g/dL were associated with a twofold risk of death when compared to the risk associated with haemoglobin levels of 10–11 g/dL.⁶³ Correction of anaemia in individuals with CKD has been positively associated with an improvement in quality of life as well as decreased mortality.⁶⁴

      The pathophysiology of anaemia of CKD and anaemia of chronic disease share many overlapping features because of the underlying inflammation present in both conditions. Inflammation leads to functional iron deficiency from deranged iron homeostasis and a limited amount of free iron available to use in the production of new RBCs. In anaemia of CKD, hepcidin levels are more elevated than in anaemia of chronic disease, which is presumably because of reduced renal clearance of the peptide, resulting in even greater functional iron deficiency. An even more pronounced deficit of renally produced erythropoietin occurs due to the intrinsic renal dysfunction, leading to reduced bone marrow stimulation and impaired RBC production. Additionally, uraemia and elevated levels of unfiltered toxins in the blood can cause uraemia‐associated platelet dysfunction, leading to increased bleeding and worsening anaemia. Toxins also shorten RBC lifespan from the typical 120 days to 30 or 40 days.⁶⁵ Individuals with CKD who are on dialysis have increased blood losses through frequent phlebotomy and haemodialysis. The cumulative effect of these mechanisms can produce severe anaemia (haemoglobin levels less than 8 ng/dL) that is frequently refractory to treatment.

      The National Kidney Foundation recommends a workup of anaemia of CKD when haemoglobin levels fall below 12 g/dL in men and 11 g/dL in women.⁶⁶ Anaemia of CKD is routinely diagnosed by laboratory studies. Typically manifesting as a normocytic, normochromic anaemia, the diagnosis requires impaired renal function as determined by glomerular filtration rate (GFR), low haemoglobin, low to normal serum iron, normal to high ferritin, low to normal transferrin saturation, and normal to high TIBC. The reticulocyte count is low in proportion to degree of anaemia (Figure 22.3). Erythropoietin production is most severely depressed once the creatinine clearance falls below 30 mL/min but also progressively decreases with a decline in creatinine clearance under the normal range (under 90 mL/min).⁶⁷ It is unclear how diagnostically useful erythropoietin levels are in anaemia of CKD, as they may be normal or even slightly increased above normal ranges but are low in proportion to the degree of anaemia present.⁶⁸ Additionally, the currently available commercial assays are unable to specifically measure biologically active erythropoietin, making their usefulness controversial.⁶⁹ Concurrent iron deficiency and anaemia of CKD is quite common, as RBC turnover is increased and bleeding losses through phlebotomy, uraemia‐associated platelet dysfunction, and haemodialysis are prominent.

Treatment of anaemia of CKD is limited to correction of any iron deficiency, if present, and administration of erythropoietin‐stimulating agents. The current target haemoglobin level for CKD patients on dialysis is 11–12 g/dL.⁷⁰ A haemoglobin level in the normal range or higher (achieved through the use of IV iron and erythropoietin) is not recommended as a target in this population because of the increased mortality seen in studies.⁷¹ This mortality is thought to be due to increased risk and incidence of thrombotic events. Unfortunately, 10–20% of patients with anaemia of CKD are resistant to the effects of erythropoietic agents.⁷² Additionally, these agents have been associated with progression of malignancy and increased mortality in cancer patients in a number of smaller studies.⁷³ For maximal effectiveness of exogenous erythropoietin, there must be enough free iron available for the bone marrow to use in erythropoiesis. Because of the severe functional iron deficiency often seen in anaemia of CKD, supplemental IV iron is frequently given at the time of erythropoietin administration with the goal of providing adequate levels of circulating iron. The ideal target level of ferritin is unknown; however, the Anaemia Work Group guidelines recommend maintaining serum ferritin around 200 ng/mL and transferrin saturation >20% in CKD patients on HD.⁷⁰ There is likely no benefit to treating with supplemental iron once the ferritin level reaches around 500 ng/mL, and at this level there is concern for iatrogenic hemochromatosis.

      In summary, anaemia of chronic kidney disease and anaemia of chronic disease share many similar features, although anaemia of chronic kidney disease is often more pronounced because of the renal dysfunction. The laboratory diagnosis is also similar in that haemoglobin is low, iron levels are normal to low, and ferritin is elevated. It can be managed with erythropoietin‐stimulating agents and frequently concurrent IV iron administration. In anaemia of chronic kidney disease, the ideal upper limit of ferritin when treating with IV iron is unknown, but it is suggested that iron not be supplemented if the ferritin level reaches 500 ng/mL.

Anaemia of clonal disorders

      A full discussion of clonal disorders is beyond the scope of this chapter. In general, the term clonal disorders refers to genetic aberrations in hematopoietic progenitor cells, which are typically in the bone marrow. These conditions include clonal haematopoiesis of indeterminate potential (CHIP), myelodysplastic syndrome (MDS), monoclonal gammopathy of undetermined significance (MGUS), aplastic anaemia, and acute myeloid dysplasia (MDS). A defining feature in anaemia of clonal disorders is stem cell mutations that lead to abnormal blood cell proliferation and progressive bone marrow failure. Diagnostic clues include the presence of macrocytic anaemia, anaemia with concurrent leukopenia, thrombocytopenia, and low to normal reticulocyte count. If suspected, a prompt referral to a haematology specialist should be made. Diagnostic confirmation is made by a bone marrow biopsy and requires cytogenetic and molecular studies.

Conclusion

In conclusion, anaemia, which is defined as a haemoglobin level less than 13 g/dL in men and less than 12 g/dL in women, frequently presents as a diagnostic challenge in older adults. While common with the ageing process, anaemia is not considered normal, and a workup should be pursued in most cases because of the association between anaemia and quality of life, morbidity, functional status, frailty, cognitive decline, depression, and fractures. Despite these positive associations, anaemia is frequently underdiagnosed and undertreated in older adults. It is typically classified by aetiology, including impaired production of RBCs (nutritional deficiencies, chronic inflammation, and clonal disorders), acute or chronic loss of RBCs (bleeding), and accelerated RBC destruction (haemolytic and sickle cell anaemia). The most common form of anaemia in older adults is anaemia of chronic disease, while the most common type of anaemia at the population level across age groups is iron deficiency anaemia. The nutritional deficiency anaemias (iron, folate, and vitamin B12 deficiency anaemia) tend to be the easiest to correct, while those due to inflammation (anaemia of chronic disease and anaemia of chronic kidney disease) are more difficult to correct because the underlying inflammation is not typically treatable. Anaemias from clonal disorders require urgent haematological specialist referral and in‐depth cytogenetic and molecular bone marrow analyses.

      Key points

       Anaemia is defined as a haemoglobin of less than 13 g/dL in men and 12 g/dL in women and occurs in 10–25% of older adults.

       Iron deficiency anaemia is diagnosed by low serum iron, low ferritin,

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