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Anaemia, diabetes, and the foot: A short review

Merlin Thomas

Anaemia is a common finding in patients with diabetes, which largely reflects the high prevalence of chronic kidney disease in this patient group (Stevens, 2012). However, even after adjusting for kidney function, people with diabetes are approximately twice as likely to have anaemia when compared to those without diabetes (Astor et al, 2002; Lorber and Reddan, 2006). By the time that the estimated glomerular filtration rate (eGFR) declines to <60 mL/min/1.73m2, up to one-in-three individuals with diabetes will have anaemia (Thomas et al, 2003; 2006). Anaemia also develops earlier, and is more severe, in those patients with diabetic kidney disease (Ishimura et al, 1998; Bosman et al, 2001).

To keep haemoglobin levels constant, the healthy kidney maintains an inverse relationship between synthesis of the haemopoietic hormone, erythropoietin and the haemoglobin concentration. However, in diabetes, this relationship is uncoupled, so that in most people with diabetes and anaemia, renal erythropoietin production is not elevated (as it should be), but instead remains – inappropriately – in the range considered normal for those without anaemia (Inomata et al, 1997; Craig et al, 2005; Thomas et al, 2005). This state may be considered to be functional erythropoietin deficiency, as while renal erythropoietin production remains intact, it is indifferent to the increased haemopoietic demands associated with systemic inflammation, functional haematinic deficiencies, erythropoietin resistance, and reduced red cell survival. Therefore, anaemia slowly develops.

Anaemia has a negative impact on a patient’s sense of well-being, impairing their ability to work and reducing quality of life, causing symptoms such as lack of energy, dizziness, breathlessness, poor appetite, impotence, reduced cognitive function, and decreased exercise tolerance (Lundin, 1989; Canadian Erythropoietin Study Group, 1990). For patients with diabetes, many of whom already have reduced capacities, a poor quality of life, and a high prevalence of comorbid macrovascular disease, anaemia comes as an unwelcome additional burden.

Anaemia may also influence the development and progression of diabetic foot disease. Endoneural hypoxia, due to reduced microvascular blood flow and altered vascular permeability, plays an important role in the progression of diabetic neuropathy. Factors that reduce endoneural oxygenation are known to accelerate nerve injury in diabetes, and falling haemoglobin levels have the potential to reduce tissue oxygenation. Certainly, anaemia is more common among patients with neuropathy (Bosman et al, 2001), particularly in those with autonomic changes, and in experimental models of diabetes, treatment with erythropoietin has been shown to protect against the development of neuropathy, as well as reverse established disease (Bianchi et al, 2004).

In small studies of patients with polyneuropathy and anaemia, treatment with erythropoietin has also been shown to improve motor nerve conduction velocity and compound muscle action potential (Hassan et al, 2003). Whether this is due to correction of anaemia or the direct neurotrophic effects of erythropoietin remains to be established. The potential for distinct neuroprotective actions are under active investigation in a range of conditions, from stroke to spinal cord injury. However, large clinical studies are required to establish any efficacy in patients with diabetic neuropathy.

Cutaneous oxygenation is also a major determinant of the risk of foot ulceration in diabetes and its outcome; indeed, diabetic foot wounds will not heal without adjuvant surgical treatment, unless the transcutaneous oxygen partial pressure is >30 mmHg (Kessler et al, 2003). Any reduction in haemoglobin level will also reduce skin and wound site oxygenation. The most well-known example is B-thalassemia minor, a condition associated with haemolytic anaemia and an increased risk of leg ulcers. However, the clinical effects of anaemia on wound healing in healthy individuals are marginal, possibly because of reduced blood viscosity, increased peripheral perfusion, vasoreactivity (Schmidt-Lucke et al, 2000), and elevated erythropoietin levels that accompany anaemia act to offset the negative effects of a reduced haemoglobin concentration. 

However, each of these compensatory responses may be impaired in diabetes, particularly in patients with established microvascular complications. 

Anaemia is a potent risk factor for critical limb ischaemia, lower extremity amputation, subsequent high level (leg or thigh) amputation, and prolonged institutionalisation following surgery (Lavery et al, 1997; van Houtum et al, 1998; Hokkam, 2009). This means that patients with diabetes and anaemia should be considered high risk, and afforded the frequent and fastidious foot screening that goes with other risk factors. However, while there is a strong rationale for correcting anaemia, currently there is no conclusive evidence that it improves clinical outcomes in patients with diabetic foot disease. 

A few case reports (Turba et al, 1992; Keast and Fraser, 2004) have documented improved healing of recalcitrant pressure sores and chronic leg ulceration following correction of anaemia. Erythropoietin may also have direct effects on immune function and angiogenesis in granulation tissue during wound healing in experimental models (Vlahakis, 2006). However, some authors have reported an increase in peripheral vascular disease in patients with diabetes receiving peritoneal dialysis and erythropoietin (Wakeen and Zimmerman, 1998). This may partly reflect confounding-by-indication (i.e. patients treated with erythropoietin who originally had anaemia). 

However, it is also possible that increases in total peripheral resistance and blood viscosity that follow the correction of anaemia may have negative effects in the diabetic foot patient. Similar actions may have contributed to a two-fold increase in strokes with darbepoetin-alfa, observed in the TREAT (Trial to Reduce Cardiovascular Events With Aranesp Therapy) study (Winkelmayer, 2011). The specific utility of anaemia correction on diabetic foot disease is yet to be tested in clinical trials using hard endpoints. 

There is no doubt that erythropoietin is a performance-enhancing drug, particularly in patients who have poor performance and reduced quality of life, and most strikingly in those patients with baseline haemoglobin levels <100 mg/dL (Johansen et al, 2012). From the perspective of a patient with diabetes and foot disease (and, therefore, cardiovascular disease, heart failure, retinopathy, etc), even a modest reduction in fatigue may be valuable. However, the purely palliative treatment of anaemia with erythropoietin is not without significant cost, both in terms of the drug itself, as well as the systematised management and follow-up programme required for its use. The recent advent of generic erythropoietins may change the balance of cost and benefits, and lead to the broader exploration of anaemia correction. The feet may be a good place to begin.

Anaemia is a common finding in patients with diabetes, which largely reflects the high prevalence of chronic kidney disease in this patient group (Stevens, 2012). However, even after adjusting for kidney function, people with diabetes are approximately twice as likely to have anaemia when compared to those without diabetes (Astor et al, 2002; Lorber and Reddan, 2006). By the time that the estimated glomerular filtration rate (eGFR) declines to <60 mL/min/1.73m2, up to one-in-three individuals with diabetes will have anaemia (Thomas et al, 2003; 2006). Anaemia also develops earlier, and is more severe, in those patients with diabetic kidney disease (Ishimura et al, 1998; Bosman et al, 2001).

To keep haemoglobin levels constant, the healthy kidney maintains an inverse relationship between synthesis of the haemopoietic hormone, erythropoietin and the haemoglobin concentration. However, in diabetes, this relationship is uncoupled, so that in most people with diabetes and anaemia, renal erythropoietin production is not elevated (as it should be), but instead remains – inappropriately – in the range considered normal for those without anaemia (Inomata et al, 1997; Craig et al, 2005; Thomas et al, 2005). This state may be considered to be functional erythropoietin deficiency, as while renal erythropoietin production remains intact, it is indifferent to the increased haemopoietic demands associated with systemic inflammation, functional haematinic deficiencies, erythropoietin resistance, and reduced red cell survival. Therefore, anaemia slowly develops.

Anaemia has a negative impact on a patient’s sense of well-being, impairing their ability to work and reducing quality of life, causing symptoms such as lack of energy, dizziness, breathlessness, poor appetite, impotence, reduced cognitive function, and decreased exercise tolerance (Lundin, 1989; Canadian Erythropoietin Study Group, 1990). For patients with diabetes, many of whom already have reduced capacities, a poor quality of life, and a high prevalence of comorbid macrovascular disease, anaemia comes as an unwelcome additional burden.

Anaemia may also influence the development and progression of diabetic foot disease. Endoneural hypoxia, due to reduced microvascular blood flow and altered vascular permeability, plays an important role in the progression of diabetic neuropathy. Factors that reduce endoneural oxygenation are known to accelerate nerve injury in diabetes, and falling haemoglobin levels have the potential to reduce tissue oxygenation. Certainly, anaemia is more common among patients with neuropathy (Bosman et al, 2001), particularly in those with autonomic changes, and in experimental models of diabetes, treatment with erythropoietin has been shown to protect against the development of neuropathy, as well as reverse established disease (Bianchi et al, 2004).

In small studies of patients with polyneuropathy and anaemia, treatment with erythropoietin has also been shown to improve motor nerve conduction velocity and compound muscle action potential (Hassan et al, 2003). Whether this is due to correction of anaemia or the direct neurotrophic effects of erythropoietin remains to be established. The potential for distinct neuroprotective actions are under active investigation in a range of conditions, from stroke to spinal cord injury. However, large clinical studies are required to establish any efficacy in patients with diabetic neuropathy.

Cutaneous oxygenation is also a major determinant of the risk of foot ulceration in diabetes and its outcome; indeed, diabetic foot wounds will not heal without adjuvant surgical treatment, unless the transcutaneous oxygen partial pressure is >30 mmHg (Kessler et al, 2003). Any reduction in haemoglobin level will also reduce skin and wound site oxygenation. The most well-known example is B-thalassemia minor, a condition associated with haemolytic anaemia and an increased risk of leg ulcers. However, the clinical effects of anaemia on wound healing in healthy individuals are marginal, possibly because of reduced blood viscosity, increased peripheral perfusion, vasoreactivity (Schmidt-Lucke et al, 2000), and elevated erythropoietin levels that accompany anaemia act to offset the negative effects of a reduced haemoglobin concentration. 

However, each of these compensatory responses may be impaired in diabetes, particularly in patients with established microvascular complications. 

Anaemia is a potent risk factor for critical limb ischaemia, lower extremity amputation, subsequent high level (leg or thigh) amputation, and prolonged institutionalisation following surgery (Lavery et al, 1997; van Houtum et al, 1998; Hokkam, 2009). This means that patients with diabetes and anaemia should be considered high risk, and afforded the frequent and fastidious foot screening that goes with other risk factors. However, while there is a strong rationale for correcting anaemia, currently there is no conclusive evidence that it improves clinical outcomes in patients with diabetic foot disease. 

A few case reports (Turba et al, 1992; Keast and Fraser, 2004) have documented improved healing of recalcitrant pressure sores and chronic leg ulceration following correction of anaemia. Erythropoietin may also have direct effects on immune function and angiogenesis in granulation tissue during wound healing in experimental models (Vlahakis, 2006). However, some authors have reported an increase in peripheral vascular disease in patients with diabetes receiving peritoneal dialysis and erythropoietin (Wakeen and Zimmerman, 1998). This may partly reflect confounding-by-indication (i.e. patients treated with erythropoietin who originally had anaemia). 

However, it is also possible that increases in total peripheral resistance and blood viscosity that follow the correction of anaemia may have negative effects in the diabetic foot patient. Similar actions may have contributed to a two-fold increase in strokes with darbepoetin-alfa, observed in the TREAT (Trial to Reduce Cardiovascular Events With Aranesp Therapy) study (Winkelmayer, 2011). The specific utility of anaemia correction on diabetic foot disease is yet to be tested in clinical trials using hard endpoints. 

There is no doubt that erythropoietin is a performance-enhancing drug, particularly in patients who have poor performance and reduced quality of life, and most strikingly in those patients with baseline haemoglobin levels <100 mg/dL (Johansen et al, 2012). From the perspective of a patient with diabetes and foot disease (and, therefore, cardiovascular disease, heart failure, retinopathy, etc), even a modest reduction in fatigue may be valuable. However, the purely palliative treatment of anaemia with erythropoietin is not without significant cost, both in terms of the drug itself, as well as the systematised management and follow-up programme required for its use. The recent advent of generic erythropoietins may change the balance of cost and benefits, and lead to the broader exploration of anaemia correction. The feet may be a good place to begin.

REFERENCES:

Astor BC, Muntner P, Levin A et al (2002) Association of kidney function with anemia: the Third National Health and Nutrition Examination Survey (1988-1994). Arch Intern Med 162: 1401–8
Bianchi R, Buyukakilli B, Brines M et al (2004) Erythropoietin both protects from and reverses experimental diabetic neuropathy. Proc Natl Acad Sci USA 101: 823–8
Bosman DR, Winkler AS, Marsden JT et al (2001) Anemia with erythropoietin deficiency occurs early in diabetic nephropathy. Diabetes Care 24: 495–9
Canadian Erythropoietin Study Group (1990) Association between recombinant human erythropoietin and quality of life and exercise capacity of patients receiving haemodialysis. BMJ 300: 573–8
Craig KJ, Williams JD, Riley SG et al (2005) Anemia and diabetes in the absence of nephropathy. Diabetes Care 28: 1118–23
Hassan K, Simri W, Rubenchik I et al (2003) Effect of erythropoietin therapy on polyneuropathy in predialytic patients. J Nephrol 16: 121–5
Hokkam EN (2009) Assessment of risk factors in diabetic foot ulceration and their impact on the outcome of the disease. Prim Care Diabetes 3: 219–24
Inomata S, Itoh M, Imai H, Sato T (1997) Serum levels of erythropoietin as a novel marker reflecting the severity of diabetic nephropathy. Nephron 75: 426–30
Ishimura E, Nishizawa Y, Okuno S et al (1998) Diabetes mellitus increases the severity of anemia in non-dialyzed patients with renal failure. J Nephrol 11: 83–6
Johansen KL, Finkelstein FO, Revicki DA et al (2012) Systematic review of the impact of erythropoiesis-stimulating agents on fatigue in dialysis patients. Nephrol Dial Transplant 27: 2418–25
Keast DH, Fraser C (2004) Treatment of chronic skin ulcers in individuals with anemia of chronic disease using recombinant human erythropoietin (EPO): a review of four cases. Ostomy Wound Manage 50: 64–70
Kessler L, Bilbault P, Ortéga F et al (2003) Hyperbaric oxygenation accelerates the healing rate of nonischemic chronic diabetic foot ulcers: a prospective randomized study. Diabetes Care 26: 2378–82
Lavery LA, Van Houtum WH, Armstrong DG (1997) Institutionalization following diabetes-related lower extremity amputation. Am J Med 103: 383–8
Lorber D, Reddan D (2006) Clinical characteristics of chronic kidney disease patients with and without diabetes: a subanalysis of the PAERI study. Clin Nephrol 66: 11–6
Lundin AP (1989) Quality of life: subjective and objective improvements with recombinant human erythropoietin therapy. Semin Nephrol 9(Suppl 1): 22–9
Schmidt-Lucke C, Glattkowski-Schäfer G, Kirchhof C et al (2000) Incidence of cutaneous vasoactivity in patients with anemia and pulmonary hypoxia. Vasa 29: 112–5
Stevens PE (2012) Anaemia, diabetes and chronic kidney disease: where are we now? J Ren Care 38(Suppl 1): 67–77
Thomas MC, MacIsaac RJ, Tsalamandris C et al (2003) Unrecognized anemia in patients with diabetes: a cross-sectional survey. Diabetes Care 26: 1164–9
Thomas MC, Cooper ME, Tsalamandris C et al (2005) Anemia with impaired erythropoietin response in diabetic patients. Arch Intern Med 165: 466–9
Thomas MC, Weekes AJ, Broadley OJ et al (2006) The burden of chronic kidney disease in Australian patients with type 2 diabetes (the NEFRON study). Med J Aust 185: 140–4
Turba RM, Lewis VL, Green D (1992) Pressure sore anemia: response to erythropoietin. Arch Phys Rehab Rehabil 73: 498–500
van Houtum WH, Lavery LA, Armstrong DG (1998) Risk factors for above-knee amputations in diabetes mellitus. South Med J 91:643–8
Vlahakis NE (2006) Is erythropoietin the key to optimize wound healing? Crit Care Med 34: 1279–80
Wakeen M, Zimmerman SW (1998) Association between human recombinant EPO and peripheral vascular disease in diabetic patients receiving peritoneal dialysis. Am J Kidney Dis 32: 488–93
Winkelmayer WC (2011) What caused excess strokes in patients randomized to darbepoetin in the trial to reduce cardiovascular events with Aranesp therapy (TREAT)?: no smoking gun. Circulation 124: 2805–8

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