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Saudi Journal of Kidney Diseases and Transplantation
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ORIGINAL ARTICLE  
Year : 2014  |  Volume : 25  |  Issue : 3  |  Page : 552-557
Prevalence of anemia in patients with type II diabetes and mild to moderate chronic kidney disease and the impact of anti-RAS medications


Department of Internal Medicine - Nephrology, Patras University Hospital, Patras, Greece

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Date of Web Publication9-May-2014
 

   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 2019 Dec 8];25:552-7. Available from: http://www.sjkdt.org/text.asp?2014/25/3/552/132178

   Introduction Top


The incidence of diabetes is increasing world-wide. Diabetic nephropathy is the most common cause of renal replacement therapy in the Western Word [1] and its incidence is increasing even in Asia, as in China. [2] Patients with diabetic nephropathy appear to have a greater risk of anemia. Moreover, it is more severe [3] and occurs at earlier stages compared with patients with non-diabetic kidney disease. [4],[5],[6] Anemia is associated with an increased risk of nephropathy [7] and predicts a faster rate of progression of renal disease in diabetic patients, [8] leading to end-stage renal disease. [9] 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. [10] 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. [11],[12],[13] However, these medications have been considered to be a potential contributing factor to the development of anemia. [14],[15] Direct renin inhibitors may have a renoprotective potential, but their impact on anemia has not been fully elucidated. [16]

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. [17],[18],[19]

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 Top


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. [20]
Table 1: Patients characteristics and laboratory values for diabetic (group A) and non-diabetic (group B) patients.

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   Statistical Methods Top


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 Top


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 Top


Previous studies have correlated the presence of anemia with relatively low EPO levels in persons with diabetes, even without advanced renal disease or uremia. [21] Anemia is a risk factor for the pathogenesis and progression of other diabetic complications such as micro- and macro-vascular angiopathy. [22] 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. [5]

Moreover, anemia may aggravate diabetic nephropathy, leading to end-stage renal disease. [7],[9] Anemia predicts a faster rate of progression of renal disease in patients with type 2 diabetes. [8] Additionally, a previous study with a small number of patients reported that correction of anemia by EPO administration may slow the progression of CKD. [23] However, there are anecdotal reports regarding the impact of anemia correction on the progression of renal disease. [17],[18]

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. [10] 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. [10]

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. [4],[5],[6] El-Achakar et al reported a higher prevalence of anemia in diabetic patients with moderate reduction in kidney function. [24] 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. [11],[12],[13] The renin-angiotensin system (RAS) has been implicated in the regulation of EPO [25] and there are laboratory data indicating that renin and angiotensin II may influence EPO secretion by the kidney. [26],[27] In addition, there are clinical studies reporting that the administration of ACE inhibitors may decrease serum EPO levels [28] and reduce Hb concentration in patients with congestive heart failure [29],[30] or renal transplant recipients. [31] Several studies in CKD patients also report that anti-RAS medications may decrease Hb levels, causing anemia. [14],[15],[32],[33]

However, there are conflicting data regarding their impact on Hb levels in patients with CKD, especially in diabetic nephropathy. [34],[35] Abu-Alfa et al reported that ACE inhibitors do not induce anemia resistant to EPO treatment in Hb patients. [36] 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. [37] 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. [38] 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. [39]

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 [34] and in accordance to other studies, [35],[36],[37],[38],[39] 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, [6],[24],[37],[38],[39] 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.

 
   References Top

1.US Renal Data System. USRDS 2005 Annual Report Atlas of End-Stage Renal Disease in United States. Bethesda MD, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, 2006.  Back to cited text no. 1
    
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3.Ishimura E, Nishizawa Y, Okuno S, et al. Diabetes mellitus increase the severity of anemia in non-dialyzed patients with renal failure. J Nephrol 1998; 11:83-6.  Back to cited text no. 3
    
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5.Babazono T, Hanai K, Suzuki K, et al. Lower haemoglobin level and subsequent decline in kidney function in type 2 diabetes adults without clinical albuminuria. Diabetologia 2006; 49:1387-93.  Back to cited text no. 5
    
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8.Keane WF, Brenner BM, de Zeeuw D, et al. The risk of developing end-stage renal disease in patients with type 2 diabetes and nephropathy: The RENAAL study. Kidney Int 2003; 63:1499-507.  Back to cited text no. 8
    
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12.Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the angiotensin- receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001;345:851-60.  Back to cited text no. 12
    
13.Siamopoulos KC, Kalaitzidis RG. Inhibition of the renin-angiotensin system and chronic kidney disease. Int Urol Nephrol 2008;40:1015-25.  Back to cited text no. 13
    
14.Cole J, Ertoy D, Lin H, et al. Lack of angiotensin II-facilitated erythropoiesis causes anemia in angiotensin-converting enzyme-deficient mice. J Clin Invest 2000;106:1391-8.  Back to cited text no. 14
    
15.Macdougall IC. The role of ACE inhibitors and angiotensin receptor blockers in the response to epoetin. Nephrol Dial Transplant 1999;14: 1836-41.  Back to cited text no. 15
    
16.Pasha Y, Gusbeth-Tatomir P, Covic A, Goldsmith D. Direct renin inhibitors: ONTARGET for success? Int Urol Nephrol 2009;41:341-55.  Back to cited text no. 16
    
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18.Drueke TB, Locatelli F, Clne N, et al. Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med 2006; 355:2071-84.  Back to cited text no. 18
    
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24.El-Achakar TM, Ohmit SE, McCulllough PA, et al. Higher prevalence of anemia with diabetes mellitus in moderate kidney insufficiency: The Kidney Early Evaluation Program. Kidney Int 2005;67:1483-8.  Back to cited text no. 24
    
25. Vlahakos DV, Marathias KP, Madias NE. The role of renin-angiotensin system in the regulation of erythropoiesis. Am J Kidney Dis 2010;56:558-65.  Back to cited text no. 25
    
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28.Fyhrquist F, Karppinen K, Honkanen T, Saijonmaa O, Rosenlöf K. High serum erythropoietin levels are normalized during treatment of congestive heart failure with enalapril. J Intern Med 1989;226:257-60.  Back to cited text no. 28
    
29.Herrlin B, Nyquist O, Sylvén C. Induction of a reduction in haemoglobin concentration by enalapril in stable, moderate heart failure: A double blind study. Br Heart J 1991;66:199-205.  Back to cited text no. 29
    
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31.Vlahakos DV, Canzanello VJ, Madaio MP, Madias NE. Enalapril-associated anemia in renal transplant recipients treated for hypertension. Am J Kidney Dis 1991;17:199-205.  Back to cited text no. 31
    
32. Mohanram A, Zhang Z, Shahinfar S, Lyle PA, Toto RD. The effect of losartan on haemoglobin concentration and renal outcome in diabetic nephropathy of type 2 diabetes. Kidney Int 2008;73:630-6.  Back to cited text no. 32
    
33.Neves PL, Baptista A, Morgado E, et al. Anemia correction in predialysis elderly patients: Influence of the antihypertensive therapy on darbepoietin dose. Int Urol Nephrol 2007;39: 685-9.  Back to cited text no. 33
    
34.Inoue A, Babazono T, Iwamoto Y. Effects of the Renin-Angiotensin system blockade on haemoglobin levels in type 2 diabetic patients with chronic kidney disease. Am J Hypertens 2008;21:317-22.  Back to cited text no. 34
    
35.Hayashi K, Hasegawa K, Kobayashi S. Effects of angiotensin-converting enzyme inhibitors on the treatment of anemia with erythropoietin. Kidney Int 2001;60:1910-6.  Back to cited text no. 35
    
36.Abu-Alfa AK, Cruz D, Perazella MA, Mahnensmith RL, Simon D, Bia MJ. ACE inhibitors do not induce recombinant human erythropoietin resistance in hemodialysis patients. Am J Kidney Dis 2000;35:1076-82.  Back to cited text no. 36
    
37.Piccoli A, Pastori G, Pierobon E, et al. Anti-renin-angiotensin-system drugs and development of anemia in chronic kidney disease. J Nephrol 2005;18:585-91.  Back to cited text no. 37
    
38.Shaheen FA, Souqiyyeh MZ, Al-Attar BA, et al. Prevalence of anemia in predialysis chronic kidney disease patients. Saudi J Kidney Dis Transpl 2011;22:456-63.  Back to cited text no. 38
[PUBMED]  Medknow Journal  
39.Bonakdaran S, Gharebaghi M, Vahedian M. Prevalence of anemia in type 2 diabetes and role of renal involvement. Saudi J Kidney Dis Transpl 2011;22:286-90.  Back to cited text no. 39
[PUBMED]  Medknow Journal  

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Correspondence Address:
Dr. Costas Fourtounas
Department of Internal Medicine - Nephrology, Patras University Hospital, Rio-Patras 26500
Greece
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DOI: 10.4103/1319-2442.132178

PMID: 24821151

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