Anaemia in Diabetic Kidney Disease: An Area For Improvement?
Mar 04, 2022
Contact: emily.li@wecistanche.com
S Thomas*, PE Stevens
Pract Diab Int January/February 2006 Vol. 23 No. 1 Copyright © 2006 John Wiley & Sons, Ltd
ABSTRACT
Kidney disease associated with diabetes is the most common cause of kidney failure. The development of kidney disease in diabetes can be associated with a dramatic increase in the risk of cardiovascular morbidity and mortality and with a significant effect on the quality of life. The focus of recent guidelines has been on the detection of kidney disease and treatment of the main drivers, namely glycaemic control and blood pressure. Only recently has the impact of anemia in the diabetes population come to the fore. We now know that anemia is more frequent in diabetic kidney disease and occurs at an earlier stage often when kidney function is only moderately impaired. Much of this anemia is undiagnosed, yet effective treatment is available and improves the quality of life, reduces symptoms, and may have major beneficial effects on cardiovascular morbidity and mortality. There is a need for heightened recognition of the importance of anemia, guidelines on screening and management, and research into optimum treatment and what benefits might accrue.
Copyright © 2006 John Wiley & Sons, Ltd.
Practical Diabetes Int 2006; 23(1): 22–26
KEYWORDS diabetes; anemia; erythropoietin; kidney disease; nephropathy
Introduction
Individuals with diabetes have an increased risk of progressive kidney disease. Indeed, kidney disease associated with diabetes is now the most common cause of kidney failure needing dialysis or transplantation. The recent increase in those with diabetes now on dialysis is most marked in those with type 2 diabetes and of older age.
The focus on kidney disease in dia[1]betes in the past has largely dealt with early detection of kidney disease and with treatments reducing the risk of development and progression of the diabetic vascular lesion such as glycaemic control, blood pressure reduction, and lipid-lowering therapy.
Although it has been known for a very long time that anemia is almost inevitable as kidney disease progresses, this aspect of kidney care in diabetes has been neglected until recently. In a UK survey of 644 patients with diabetes and significant renal impairment (mean estimated glomerular filtration rate [GFR] almost equal to 30ml/min) who were not known to have renal ser[1]vices, 114 (17.7%) patients had not had a hemoglobin (Hb) level checked. The prevalence of anemia by the World Health Organization (WHO) definition in the remaining 530 was around 60% and a quarter of men and women had Hb levels of <11g/dl.1
Two main developments are increasing our awareness of this important area in patients with diabetes. Since the late 1990s increasing work has demonstrated that patients with diabetes and kidney disease have an increased risk of anemia. Secondly, much previously under-diagnosed kidney disease is now being recognized with increased screening for diabetic kidney disease and a move towards the use of estimated GFR as a measure of kidney impairment. The GFR provides the best measure of the severity of kidney damage and kidney disease is now classified according to the level of GFR (Table 1).
Estimated GFR
In the past, GFR has been calcu[1]lated by a relatively inconvenient method of collecting blood and urine samples over several hours. As a result, it has been an impractical and rarely performed procedure in those with diabetes outside specialist research centers.
Most clinicians have therefore relied upon the measurement of serum creatinine alone to give an idea of kidney function. This has several drawbacks. Serum creatinine is mainly produced by the metabolism of creatine in muscle and the production of serum creatinine is therefore dependent upon the amount of body muscle. Serum creatinine production is, consequently, usually a lot higher in younger people, in males, and in blacks as compared to whites.
These limitations mean that in data from Guy's and St Thomas as many as 40% of individuals with a significantly decreased GFR have a serum creatinine within the 'normal laboratory range' and up to 20% will have stage 3 kidney disease with 'normal' serum creatinine. This will be particularly true in older individuals, females, and in whites.
These problems have prompted a move towards the use of equations to estimate GFR. There are many such equations but the most common equation now in use is the 'abbreviated MDRD equation' which incorporates the major effects that alter serum creatinine production namely age, gender, and ethnicity.2 Many laboratories now routinely report an estimated GFR where a serum creatinine is requested if these variables are provided.
Anemia in kidney disease in diabetes
WHO defines anemia as a Hb level of <12g/dl in pre-menopausal females, and <13g/dl in adult males and post-menopausal females.
Using this definition Thomas et al. reported that in a cross-sectional survey of 820 patients with diabetes in Australia around a quarter of patients had unrecognized anemia.3 Comparing their data to other studies, they found that the prevalence of anemia in those with diabetes was two to three times higher than for patients with similar kidney damage in the general population. The anemia predictably gets worse as the kidney damage progresses and, in particular, Hb levels were significantly lower in all patients with esti[1]mated GFRs of <70ml/min compared with higher levels of GFR.4
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Pathogenesis of anemia in kidney disease in diabetes
Erythropoietin
Erythropoietin (EPO) deficiency is the primary cause of renal anemia. EPO is a hormone produced primarily by the kidney and is responsible for the regulation of red blood cell production (Figure 1).
It is striking that anaemia in diabetic kidney disease develops at higher levels of GFR compared to non-diabetic renal disease, and not infrequently develops while the serum creatinine level remains in the 'normal' range. However, as with anemia in non-diabetic patients, the level of Hb falls as the GFR falls and is associated with a relative lack of EPO response (Figure 2).
The precise mechanisms leading to early EPO-deficiency anemia in patients with diabetes have yet to be fully elucidated (Table 2). In type 1 diabetes particularly, anemia is more common in females in early diabetic kidney disease but this is not because of reduced iron stores.5 The presentation of EPO-depleted anemia in association with autonomic neuropathy,6,7 and particularly altered sympathetic function, supports the concept of autonomic neuropathy as a contributor. Although ACE inhibition may reduce EPO levels,8 clinical studies do not suggest this is a major contributor to anemia in patients with diabetes.9 Urinary EPO losses and inter[1]stitial fibrosis in diabetic kidney disease are also possible contributors.
The role of iron
The availability of iron is crucial for red blood cell production. The most commonly used methods to detect iron deficiency are serum ferritin and transferrin saturation (TSAT). Serum ferritin measures iron stores, but this iron may not be freely available for red blood cell production. The traditional understanding of iron deficiency is of an 'absolute iron deficiency' usually related to blood loss or poor dietary intake/absorption when iron stores are depleted, such that ferritin levels are <20µg/L. Functional iron deficiency describes the situation where ferritin levels are 'normal' but insufficient 'free' iron is available for red cell production. Put simply, iron treatment may well be effective and a necessary part of anemia treatment in those with diabetes and kidney disease, even though they may not have the 'traditional absolute' iron deficiency.
Diagnosis and treatment of anemia in diabetic kidney disease
Detection and diagnosis
The patient with anemia may be asymptomatic or have symptoms such as tiredness, lethargy, and dizziness that may be attributed to other causes of diabetes. There are no guidelines on the frequency of testing for anemia, but it is our practice to check a full blood count yearly in early kidney disease and at each visit in those with an estimated GFR <50ml/min. For the purposes of management, anemia is defined as a Hb level of <11g/dl in pre[1]menopausal females, and <12g/dl in adult males and post-menopausal females.10,11 Other causes of anemia should be looked for and actively excluded and any iron deficiency, both absolute and functional, in anemic patients should be rectified prior to commencing EPO therapy.
Therefore assessment of anemia should at least include measurement of full blood count and measurement of iron. Many would routinely measure vitamin B12 and folate levels. Renal anemia is generally normochromic and not [1]mocytic. The presence of microcytosis or macrocytosis should prompt a search for other causes of anemia.
In patients with non-renal anemia, serum EPO levels are elevated in response to falling Hb levels (Figure 2). If no cause other than chronic kidney disease has been found following evaluation for anemia, it is likely that anemia is due to EPO deficiency and measure[1]ment of serum EPO levels is rarely necessary.
Iron management
Treatment of anemia with recombinant EPO requires adequate iron stores and an adequate supply of 'available' iron. Functional iron deficiency is common in patients receiving EPO treatment and it is therefore important that iron deficiency is treated prior to the commencement of EPO, and that iron stores are maintained. Commonly used measures of functional iron deficiency include transferrin saturation and percentage of hypochromic red cells.12 (Table 3.)
Oral iron preparations are usu[1]ally ineffective and may contribute to unwanted gastrointestinal side effects, which are common in dia[1]betes, and our practice is to largely avoid them. Parenteral iron is therefore the treatment of choice for functional iron deficiency. The intro[1]duction of ferric sodium gluconate and iron saccharate has significantly reduced the risks of life-threatening allergic reactions, but there are some concerns that they may predispose to infection so in our practice we avoid them during active infections – e.g. infected foot ulcers.
If the iron status is satisfactory and other causes of anemia have been excluded but the anemia persists, then EPO therapy should be considered.
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Targets for treatment
The level of initial intervention and the target Hb concentration remain uncertain in diabetes. Most guide[1]lines, largely based on non-diabetic populations, currently support the correction of anemia to a Hb level between 10 and 11g/dl. Target levels of between 11 and 12 g/dl have been suggested in small studies on postural hypotension.13–15
Practicalities of treatment
Anemia management involves monitoring and maintenance of Hb and iron levels, blood pressure, and coordination of the delivery of supplies between primary and secondary care. It has traditionally come under the umbrella of anemia specialist nurses/coordinators typically working in renal units as it has largely been confined to those on dialysis or having advanced renal failure.
Dependent upon the numbers involved in any one center this may be the best way forward or other arrangements may be required. In some areas, this service is being set up in primary care in a similar way to insulin starting moving increasingly out to the community.
EPO treatment is a self-administered injection via a pen device. In our experience, often comparatively small doses are needed usually no more than once a week in the early stages when kidney dysfunction is mild/moderate. Individuals using insulin usually find the step technically very straightforward although it is another injection.
Intravenous iron is given as an infusion usually weekly to build up initial levels and then maybe every couple of months; this usually happens in a hospital setting and is occasionally problematic in those individuals with multiple complications and poor venous access.
What are the benefits of treatment?
Untreated anemia has adverse consequences ranging from effects on quality of life, cognitive function, and libido to increased mortality and morbidity, with its associated economic burden.
Chronic kidney disease is associated with increased mortality and morbidity from all forms of cardiovascular disease and patients with diabetes are at particularly increased risk16 such that cardiovascular mortality in the dialysis population is between 40 and 47 times higher in those with diabetes and advanced kidney failure than in the general population.17 One of the earliest manifestations of heart disease in chronic kidney disease and diabetes is left ventricular hypertrophy (LVH).18,19 LVH is a feature at the stage of microalbuminuria20 and increases in proportion to the progression of kidney disease in patients with type 2 diabetes.
Levin et al.21 studied 246 patients with early kidney disease, 63 of whom also had diabetes. They found that a fall in Hb of 0.5g/dl was associated with an odds ratio of 1.32 for an increase in left ventricular growth, while an increase in systolic blood pressure of 5mmHg had an odds ratio of 1.11.
In patients on dialysis from all-cause large observational studies, anemia is associated with increased mortality rates and increased hospitalisation.22,23
Improvements in cardiac function and mortality are to be expected from the treatment of anemia in diabetes, but there is at present a lack of randomized controlled trials to confirm this and most of the data are currently observational. In small studies, the other clinical benefits of correcting anemia with EPO therapy include improved exercise capacity, improved cognitive function, a better quality of life, and increased libido. Much of the evidence derives from studies on dialysis patients. Correction of anemia with EPO increases work capacity in both patients receiving dialysis and in pre-dialysis patients. Improvements in the quality of life of patients have also been clearly shown.24–27
There are several small studies in diabetes suggesting that recombinant EPO therapy is effective, safe, and well-tolerated in the correction of anemia associated with diabetes.28,29 The Hb response to EPO treatment has been rapid and maintained, and as good as that in non-diabetic patients with chronic kidney disease. All studies report improved patient well-being. In those patients with autonomic neuropathy and symptomatic postural hypotension, significant improvements in standing blood pressure and reduction of symptomatic postural hypotension were observed following EPO treatment, albeit with some increase also in supine hypertension. Anecdotally, we have on occasion also noted a reduction in admissions with gastroparesis when associated anemia was treated in conjunction with other measures.
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Adverse effects
Reported adverse effects of EPO therapy have included hypertension, hyperkalemia, flu-like symptoms, pain and irritation around the injection site, and pure red cell aplasia (a rare adverse event nearly all in association with one formulation that has now been withdrawn).
The use of anti-hypertensive drugs is up to 21% higher in patients treated with EPO therapy but these adverse effects rarely cause significant clinical problems.
Whether or not an early and effective treatment of anemia translates into improved outcomes in patients with diabetes remains to be seen. The limited experience of the treatment of anemia in this patient group prompts the need for more clinical data on anemia correction in early diabetic kidney disease, especially with respect to cardiovascular outcomes.
Conclusions
Anemia occurs early in the course of kidney complications of diabetes, often well before referral to nephrology services. Recognition of this clinical problem may prevent unnecessary investigation for other causes of anemia and offer beneficial effects on quality of life and patient well-being. Anemia treatment in diabetes is effective, safe, and well-tolerated. Although not yet part of national guidelines, anemia should be considered more in diabetes care.
Key points
• Anaemia in kidney disease in diabetes is often not recognized and frequently not managed although it may contribute to the excess morbidity and mortality seen in the disease
• Anaemia may be more severe and occur at an earlier stage in those with diabetic kidney disease as compared with other kidney diseases. This may be related to the co-existence of autonomic neuropathy
• Failure of erythropoietin production is the major cause of anemia associated with diabetic kidney disease
• 'Functional' iron deficiency is common in anemia of kidney disease and ensuring 'adequate' iron is essential in the treatment of anemia of kidney disease and should be undertaken before erythropoietin is used.
• Treatment of anemia may, in addition to improving quality of life, have significant benefits in those with autonomic neuropathy and symptomatic postural hypotension
• Target levels of hemoglobin in those on treatment with erythropoietin should be between 10 and 11g/dl
Conflict of interest statement
Both authors have acted as advisors to Roche who makes one of the erythropoiesis-stimulating agents.
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