Erythropoietin response to anemia and its association with autonomic neuropathy in type 2 diabetic patients without advanced renal failure
Introduction
Erythropoietin (EPO) is produced by the interstitial cortical cells of the kidney. Patients with advanced renal failure [glomerular filtration rate (GFR) <40 ml/min/1.73 m2] typically develop anemia because of impaired production of EPO by the kidneys (Radtke et al., 1979).
Anemia is often more severe and occurs at an earlier stage in patients with diabetic nephropathy than in patients with other types of chronic kidney disease (Symeonidis et al., 2006). However, the cause of anemia in diabetic patients without advanced renal failure is unclear. Anemia consequent to EPO deficiency has been described in these patients. Bosman, Winkler, Marsden, Macdougall, and Watkins (2001) compared 27 patients with type 1 diabetes and diabetic nephropathy with 26 patients with glomerulonephritis. They reported that anemia was more prevalent in diabetic patients than in glomerulonephritis patients and that serum EPO levels of patients with diabetic nephropathy did not increase in response to anemia, whereas those of patients with iron deficiency anemia did. Bruno et al. (2006) demonstrated that EPO production in 18 microalbuminuric type 2 diabetic patients with normal renal function was sufficient to maintain normal hemoglobin (Hb) concentrations. Spallone et al. (2004) reported that there was no relationship between EPO and Hb levels in 64 type 2 diabetic patients without overt nephropathy. It was also suggested that autonomic neuropathy might contribute to EPO deficiency (Spallone et al., 2004). However, all the studies mentioned above were limited by the small number of subjects.
In this study, we investigated EPO response to anemia and its association with autonomic neuropathy in type 2 diabetic patients without advanced renal failure.
Section snippets
Patients and sample collection
Three hundred seventeen subjects with type 2 diabetes who were admitted to the diabetes clinic at St. Mary's Hospital in Seoul, Korea, were consecutively recruited between March 2006 and June 2008. We excluded patients with acute febrile infections such as urinary tract infections or active foot ulcers, significant hepatic or hematopoietic abnormalities, cardiac arrhythmia, previous histories of gastrectomy, and iron- or vitamin-deficiency anemia. On the basis of these criteria, 68 patients
Clinical characteristics of diabetic patients
The clinical characteristics of the diabetic patients are summarized in Table 1. For diabetic patients without advanced renal failure, the mean age was 60.6 years and the mean duration of diabetes was 12.3 years. Eighty-four patients (39.8%) were treated with insulin, 116 (55.0%) with metformin, and 24 (11.4%) with thiazolidinedione. One hundred thirty-four patients (63.5%) were normoalbuminuric, 49 (23.2%) were microalbuminuric, and 28 (13.3%) were macroalbuminuric. For diabetic patients with
Discussion
This study provides evidence that some type 2 diabetic patients without advanced renal failure had a blunted EPO response to anemia, which was associated with autonomic neuropathy.
We found that the inverse relationship between EPO and Hb levels in diabetic patients without advanced renal failure was preserved. Multiple linear regression analysis also revealed that EPO level was an independent predictor of Hb level in these patients. However, EPO levels were inappropriately low compared with
References (18)
- et al.
Circulating erythropoietin in microalbuminuric type 2 diabetic patients with normal renal function: A pilot study
Journal of Diabetes and Its Complications
(2006) - et al.
Anemia and the role of erythropoietin in diabetes
Journal of Diabetes and Its Complications
(2006) - et al.
Serum erythropoietin concentration in chronic renal failure: Relationship to degree of anemia and excretory renal function
Blood
(1979) - et al.
The anemia of primary autonomic failure and its reversal with recombinant erythropoietin
Annals of Intern Medicine
(1994) - et al.
Erythropoietin response to hypoxia in patients with diabetic autonomic neuropathy and non-diabetic chronic renal failure
Diabetic Medicine
(2002) - et al.
Anemia with erythropoietin deficiency occurs early in diabetic nephropathy
Diabetes Care
(2001) - et al.
American Diabetes Association. Diabetic neuropathies: A statement by the American Diabetes Association
Diabetes Care
(2005) - et al.
Hepcidin: A molecular link between inflammation and anaemia
Nephrology, Dialysis, Transplantation
(2004) Analysis of heart rate variability and other non-invasive tests with special reference to diabetes mellitus
Cited by (14)
SGLT2 inhibitors and the autonomic nervous system in diabetes: A promising challenge to better understand multiple target improvement
2021, Diabetes and MetabolismCitation Excerpt :Early dysregulation of EPO production (before the development of clinical nephropathy) has been found in T2D patients and is characterized by loss of the physiologically negative relationship between EPO and haemoglobin together with an independent association between autonomic neuropathy severity and haematocrit [50]. This finding was confirmed by another study of T2D patients [51], and prompted the suggestion of the implication of autonomic neuropathy in this early abnormality independently of microalbuminuria and estimated glomerular filtration rate (eGFR) [50,51]. More recently, the attention focused on the role of renal innervation shifted so as to now include the effects of the enhanced activity of afferent sensory nerves and downstream systemic sympathetic hyperactivity found in hypertension and T2D, but also in heart failure and chronic renal failure [52,53].
Genetic disposition and modifiable factors independently associated with anemia in patients with type 2 diabetes mellitus
2015, Diabetes Research and Clinical PracticeCitation Excerpt :In vitro experiments by Tong et al. have shown that a single nucleotide change from G to T in EPO promoter (rs1617640) can alter the EPO mRNA levels [10]. However, in patients with type 2 diabetes, functional erythropoietin deficiency and hyporesponsiveness are thought to contribute to anemia [19], and serum erythropoietin levels were only weakly correlated with hemoglobin level [20]. Therefore, the association between EPO SNP and anemia in our study may be due to mechanisms more complicated than simple changes in EPO gene expression or protein levels.
Peripheral neuropathy response to erythropoietin in type 2 diabetic patients with mild to moderate renal failure
2012, Clinical Neurology and NeurosurgeryCitation Excerpt :Recent studies have shown that α2γ1 subunits of voltage gate calcium channels are upregulated in streptozotocin-induced diabetic neuropathy [22], and gabapentin, by inhibiting these channels [23], causes decreased neural activity [24]; therefore, gabapentin has been commonly used to relieve diabetic neuropathy [8]. The beneficial effect of EPO on autonomic neuropathy and polyneuropathy in patients with moderate to severe diabetic neuropathy has been demonstrated by some researchers [18,19]. In this study, we assessed the effect of addition of EPO to gabapentin on the electrophysiological and clinical findings of lower extremities nerve function in patients with mild to moderate renal failure and diabetic neuropathy.
Global Prevalence of Anemia Among Type 2 Diabetic Adult Patients: A Systematic Review and Meta-Analysis
2023, Diabetes, Metabolic Syndrome and ObesityThe Relationship between Erythrocytes and Diabetes Mellitus
2021, Journal of Diabetes ResearchRecent Developments in Research on Anemia and Microvascular Complications in Patients with Type 2 Diabetes Mellitus
2020, Chinese General Practice
- 1
These authors equally contributed to this work.