| Abstract|| |
Anemia is a common feature of diabetes and chronic kidney disease (CKD) mainly due to erythropoietin (EPO) deficiency and uremic toxicity. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) have been established as first-choice medications for the treatment of diabetic nephropathy. However, there are conflicting data regarding their impact on hemoglobin levels in patients with diabetic nephropathy. We evaluated the prevalence of anemia in 101 patients with diabetes mellitus type II and CKD at stage III-IV (group A) compared with 101 non-diabetic patients with similar renal function (group B). Moreover, we evaluated the impact of ACE inhibitors and ARBs on patients' anemia. Anemia was observed in 60 patients in group A and in 47 patients in group B (P < 0.01). Thirty-one (31) patients in group A and 19 patients in group B were receiving exogenous EPO for correction of renal anemia (P <0.05). Mean values of hemoglobin did not show significant differences (12.5 ± 1.8 vs 12.6 ± 1.7 g/dL) between the two groups. Seventy-five patients in group A and 52 patients in group B were receiving ACE inhibitors and/or ARBs (P <0.01), but, after multivariate analysis, we could not detect any association between anemia and the prescription of these medications. Anemia is more common in diabetic patients with CKD stage III-IV than in non-diabetic patients with similar renal function. Our results indicate that ACE inhibitors and ARBs are not a significant cause of anemia for both populations.
|How to cite this article:|
Dousdampanis P, Trigka K, Fourtounas C. Prevalence of anemia in patients with type II diabetes and mild to moderate chronic kidney disease and the impact of anti-RAS medications. Saudi J Kidney Dis Transpl 2014;25:552-7
|How to cite this URL:|
Dousdampanis P, Trigka K, Fourtounas C. Prevalence of anemia in patients with type II diabetes and mild to moderate chronic kidney disease and the impact of anti-RAS medications. Saudi J Kidney Dis Transpl [serial online] 2014 [cited 2020 Jul 15];25:552-7. Available from: http://www.sjkdt.org/text.asp?2014/25/3/552/132178
| Introduction|| |
The incidence of diabetes is increasing world-wide. Diabetic nephropathy is the most common cause of renal replacement therapy in the Western Word  and its incidence is increasing even in Asia, as in China.  Patients with diabetic nephropathy appear to have a greater risk of anemia. Moreover, it is more severe  and occurs at earlier stages compared with patients with non-diabetic kidney disease. ,, Anemia is associated with an increased risk of nephropathy  and predicts a faster rate of progression of renal disease in diabetic patients,  leading to end-stage renal disease.  The pathogenesis of anemia in patients with chronic kidney disease (CKD) due to diabetes is multifactorial. Disturbed erythropoietin (EPO) synthesis and the uremic toxins accumalated represent the main factors in the development of anemia in CKD. Moreover, in diabetic nephropathy, there are additive diabetes-related events that lead to the development of anemia, such as tubulointerstitial damage, which results in the impaired production of EPO by peritubular fibroblasts, chronic inflammation, oxidative stress, autonomic neuropathy, impaired function of NO and elevated levels of advanced glycosylation products.  The benefit of the angiotensin-converting enzyme (ACE) inhibitors and the angiotensin receptor blockers (ARBs) in the outcome of diabetic nephropathy is now well recognized. ,, However, these medications have been considered to be a potential contributing factor to the development of anemia. , Direct renin inhibitors may have a renoprotective potential, but their impact on anemia has not been fully elucidated. 
At present, there is no clear consensus on the optimal level of hemoglobin (Hb) in patients with CKD and diabetes. Early treatment of anemia may reduce cardiovascular morbidity and improve quality of life. Nevertheless, some recent large studies reported increased mortality with high Hb levels, with no beneficial effect on the progression of CKD. ,,
The aim of this cross-sectional study was to investigate the prevalence of anemia in patients with CKD stage III-IV due to diabetic nephropathy compared with patients with non-diabetic renal disease and to evaluate the impact of ACE-inhibitors and ARBs on patients' anemia.
| Materials and Methods|| |
The studied population consisted of 101 patients (70 males, 31 females) with diabetes mellitus type II and diabetic nephropathy (group A) and 101 patients (71 males, 30 females) with non-diabetic kidney disease. All patients had CKD stage III-IV and they were under follow-up for at least six months in the pre-dialysis clinic in Patras University Hospital between 1999 and 2005.
Exclusion criteria included previous history of recent blood loss, recent history of transfusion, iron deficiency anemia (serum ferritin <100 ng/mL), previous history of malignancy or hematologic disorders, previous or current history of immunosuppressive therapy and polycystic kidney disease. Both groups were matched for age and renal function, although diabetic patients tended to have a higher body mass index (BMI). Patient characteristics and laboratory values are shown in [Table 1]. Diabetes mellitus type II was diagnosed by self-report, fasting glucose levels >125 mg/dL or non-fasting glucose >200 mg/dL. The diagnosis of diabetic nephropathy was based on the presence of clinical features, including previous history of diabetes type II, proteinuria, hypertension, diabetic retinopathy and the absence of signs of secondary renal disease such as hematuria and active urinary sediment. Six-months average Hb values were used for statistical analysis. Anemia was defined according to the K/DOQI guidelines with Hb values <12.0 g/dL for men and post-menopausal women (>50 years old) and <11.0 g/dL for pre-menopausal women (<50 years old), or the need for exogenous recombinant EPO administration. All the patients were classified in III to IV stages according to the K/DOQI clinical practice guidelines for CKD based on the estimation of glomerular filtration rate (eGFR) by the chronic kidney disease epidemiology collaboration (CKD-EPI) equation. 
|Table 1: Patients characteristics and laboratory values for diabetic (group A) and non-diabetic (group B) patients.|
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| Statistical Methods|| |
Data were analyzed by the non-parametric chi-square test, Mann-Whitney U test and multiple regression analysis as appropriate. P-values <0.05 were considered statistically significant.
| Results|| |
Anemia was observed in 60 patients with diabetic nephropathy in group A and in 47 non-diabetic patients in group B (P <0.01).
Thirty-one patients in group A and 19 patients in group B were receiving EPO for correction of renal anemia (P <0.05).
However, mean values of hemoglobin did not show significant differences (12.5 ± 1.8 vs 12.6 ± 1.7 g/dL) between the two groups, probably due to correction of low initial Hb values by exogenous EPO administration.
Seventy-five patients in group A and 52 patients in group B were receiving ACE inhibitors, or ARBs (P <0.01). However, in a multivariate analysis model including age, EPO administration and renal function, these medications failed to become independent predictors of Hb in both groups.
| Discussion|| |
Previous studies have correlated the presence of anemia with relatively low EPO levels in persons with diabetes, even without advanced renal disease or uremia.  Anemia is a risk factor for the pathogenesis and progression of other diabetic complications such as micro- and macro-vascular angiopathy.  Detection of anemia in diabetic patients, even without clinical albuminuria, may identify patients at high risk of progressive renal disease and also patients with a higher risk of adverse clinical outcomes. 
Moreover, anemia may aggravate diabetic nephropathy, leading to end-stage renal disease. , Anemia predicts a faster rate of progression of renal disease in patients with type 2 diabetes.  Additionally, a previous study with a small number of patients reported that correction of anemia by EPO administration may slow the progression of CKD.  However, there are anecdotal reports regarding the impact of anemia correction on the progression of renal disease. ,
The etiology of anemia in diabetes is multi-factorial. Chronic hyperglycemia may lead to hypoxia in the renal interstitium, resulting in tubulointerstitial damage and impaired production of erythropoietin by the peritubular fibroblasts.  Inappropriately low EPO levels in diabetes may lead to earlier development of anemia. Other factors that may contribute to anemia in diabetic nephropathy are: Chronic inflammation, elevated levels of advanced glycosylation end products, diabetic neuropathy and inadequate iron stores. 
Previous studies reported that the incidence of anemia in diabetic patients is higher, occurs at earlier stages of CKD and is more severe compared with that of patients with non-diabetic kidney disease. ,, El-Achakar et al reported a higher prevalence of anemia in diabetic patients with moderate reduction in kidney function.  Our experience confirms these findings. Anemia was observed in 60 patients in group A and in 47 non-diabetic patients in group B (P <0.01). Regarding the severity of anemia, 31 patients in group A and 19 patients in group B were receiving EPO for correction of renal anemia (P <0.05). The number of patients in whom anemia required management with EPO administration was higher in patients with diabetic CKD (group A) compared with non-diabetic patients (group B), reflecting the higher grade of severity of anemia in diabetic patients. Mean values of Hb did not show significant differences (12.5 ± 1.8 vs 12.6 ± 1.7 g/dL) between the two groups, probably due to correction of the lower initial Hb values by exogenous EPO.
ACE inhibitors and, more recently, ARBs have been established as first-line medications for the treatment of diabetic nephropathy and their benefit on proteinuria is well recognized. ,, The renin-angiotensin system (RAS) has been implicated in the regulation of EPO  and there are laboratory data indicating that renin and angiotensin II may influence EPO secretion by the kidney. , In addition, there are clinical studies reporting that the administration of ACE inhibitors may decrease serum EPO levels  and reduce Hb concentration in patients with congestive heart failure , or renal transplant recipients.  Several studies in CKD patients also report that anti-RAS medications may decrease Hb levels, causing anemia. ,,,
However, there are conflicting data regarding their impact on Hb levels in patients with CKD, especially in diabetic nephropathy. , Abu-Alfa et al reported that ACE inhibitors do not induce anemia resistant to EPO treatment in Hb patients.  Piccoli et al, in a retrospective study, observed that anti-RAS drugs did not influence the development of anemia in patients with mild to severe CKD.  Shaheen et al have also reported in a recent cross-sectional multi-center study that even though diabetic CKD patients presented with anemia more often (54%) than non-diabetic CKD patients (31%, P = 0.004), treatment with anti-RAS inhibitors was not associated with the prevalence of anemia.  Finally, Bonakdaram et al have not found any correlation between the use of anti-RAS medications and the prevalence of anemia in a large cohort of 1962 diabetic Iranian patients. 
In our study, 75 patients in group A and 52 patients in group B were receiving ACE inhibitors or ARBs (P <0.01). Nevertheless, in a multivariate model, these medications failed to become independent predictors of Hb levels in either group. In contrast to the study of Inue et al  and in accordance to other studies, ,,,, our data suggest that ACE inhibitors and ARBs are not a significant cause of anemia for both patient populations. Their probable impact on the development of anemia is dose-dependent and in low doses they do not cause anemia. Our policy is not to exceed maximum recommended doses of ACE inhibitors or ARBs, and no patient was under dual anti-RAS blockade. Further studies are needed to investigate the potential role of ACE inhibitors and ARBs in the pathogenesis and development of renal anemia.
Our study had several limitations. First, this is a single center report and our sample size was rather small. Second, as in every cross-sectional study, no definite conclusions can be made regarding real causality between the studied parameters, and there is always the problem of bias by indication. Third, we did not report the exact doses of administrated EPO in both groups. Fourth, by applying several exclusion criteria, the studied population may not accurately reflect real clinical practice and the average CKD patient (diabetic or non-diabetic) followed-up in the renal clinic. Finally, we had no data regarding the possibility of functional iron deficiency (transferrin saturation) in our patients, although all of them had serum ferritin levels above the suggested threshold (>100 ng/mL)
In conclusion, our findings in agreement with previous studies, ,,,, indicate that anemia is more common in diabetic patients with CKD stage III-IV than in non-diabetic patients with similar levels of renal function. Anti-RAS medications (ACE inhibitors and ARBs) do not appear to be a significant cause of anemia in these patient populations.
Conflicts of Interest: None to declare.
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Dr. Costas Fourtounas
Department of Internal Medicine - Nephrology, Patras University Hospital, Rio-Patras 26500