Factors Related to the Presence of Anemia in Patients with Chronic Kidney Disease in Hemodialysis

  

    
Variable
    
OR
    
CI 95%
    
p
  
  

    
Male gender
    
1.62
    
1.17-2.25
    
0.003
  
  

    
Female gender
    
0.65
    
0.47-0.90
    
0.010
  
  

    
Diabetes mellitus
    
1.53
    
1.06-2.22
    
0.022
  
  

    
Glomerulopathies
    
0.67
    
0.32-1.42
    
0.305
  
  

    
Hypophosphatemia
    
0.55
    
0.27-1.10
    
0.096
  
  

    
Hyperphosphatemia
    
1.25
    
0.86-1.83
    
0.229
  
  

    
Calcium-phosphate product >55mg2/dl2
    
1.20
    
0.79-1.82
    
0.388
  
  

    
Iron deficiency
    
2.36
    
0.91-6.13
    
0.076
  
  

    
Absolute iron deficiency
    
1.18
    
0.51-2.71
    
0.689
  
  

    
Serum transferrin <170 mg/dl
    
0.88
    
0.47-1.66
    
0.712
  
  

    
Serum transferrin <200 ng/dl
    
1.93
    
1.25-2.98
    
0.003
  
  

    
Serum ferritin >500 ng/dl
    
1.12
    
0.59-2.12
    
0.726
  
  

    
Erythropoietin administration
    
0.65
    
0.44-0.95
    
0.028
  

Table 4: Multivariate analysis. Anemia in HD patients (n=747).

Discussion

The results in this study show a higher frequency of Hb below the recommended value in patients receiving HD at IMSS. Male gender, diabetes and iron deficiency assessed by the serum ferritin levels were the independent risk factors for Hb below the cutoff value.

Anemia is a significant risk factor for cardiovascular comorbidity and cognitive impairment with repercussions on the quality of life [11-20]. For these reasons, it is considered an indicator to optimize treatment and reduce the complications associated with HD. Studies in other populations have acknowledge the presence of anemia in more than 70% of Stage 5 CKD patients [21]. In our study, we found that 94.2% of the patients have anemia according to the definition established by the KDIGO and the WHO. On the other hand, when analyzing the proportion of patients with hemoglobin levels <10 g / dl, as anemia was defined in our study, we identify that 56% of the patients do not meet the hemoglobin target according to the KDIGO guideline recommendations [22]. The GCC-DOPPS (Gulf Cooperation Council - Dialysis Outcomes and Practices Patterns Study) which included 927 patients in HD, reported mean values of Hb in 10.9 g/dl, ferritin 390 ng/dl, transferrin saturation 28.4% and EPO dose of 8667 UI per week [23]. In our population, the average level of Hb was lower (9.7 g/dl), as were the iron-status indicators (ferritin 327 ng/dl, transferrin saturation 25.29%), and higher doses of EPO were used per week (10 097 UI). Regarding the anemia management, the GCC-DOPPS reported broader prescription of Erythropoiesis Stimulating Agents (ESA), 88 vs. 78.8%; higher IV iron dose, 53% vs. 12.4%; and lower oral iron use 20% vs. 56.8% with respect to our population.

In this study, Diabetes Mellitus (DM) is recognized as a risk factor for Hb beneath the cutoff limit, a value that persisted through the multivariate analysis. Loutradis and cols [24] encountered a higher prevalence of anemia in diabetic patients (47.8% vs. 33.2%, p=0.004) and DM was an independent risk factor for the development of anemia in a study with 368 CKD patients: 184 with DM and 184 without DM (OR 2.20, CI 95% 1.19-4.06).

In the DOPPS work conducted with patients in HD, it was found that the probability of attaining Hb level ≥11 g/dl was associated with mineral metabolism. For every 1 mg/dl rise in serum calcium the OR was 1.32, CI 95% 1.25-1.40, p=0.0001, for phosphorus OR 1.08, CI 95%, 1.05-1.11, p=0.0001, while each 100 pg/ml increment in PTH concentration had a protective factor OR 0.96, Ci 95% 0.95-0.98, p=0.0001 [25]. An inverse association was found in a more recent study performed by Boronat and cols with Stage 4 and 5 CKD patients [26]. For each 1mg/dl rise in calcium levels the OR was 0.29, CI 95% 0.16-0.49, p=0.0001, and the presence of anemia was greater with the increasing phosphorus. For each 1 mg/dl increase in phosphorus the OR was 2.19, CI 95% 1.55-3.15, p=0.001. In our study, serum phosphorus >4.5 mg/dl (OR 1.69, CI 95% 1.21-2.28, p=0.001) and calcium phosphate product >55 mg2/dl2 (OR 1.43, CI 95% 1.01- 2.03, p=0.04) were recognized as risk factors for Hb below the cutoff value and serum phosphorus <2.5 mg/dl was the only protective factor (OR 0.44, CI 95% 0.23-0.83, p=0.012). Unlike the commented studies, ours could not establish an association between anemia and hyperparathyroidism (OR 1.59, CI 95% 0.81-3.01, p=0.153); nevertheless, it is important to indicate that PTH concentration levels were only available in 22% of patients.

Iron deficiency anemia is a common complication for CKD patients and has been identified as a cause for ESA resistance [27]. We found iron deficiency (OR 1.95, CI 95% 1.38-2.75, p=0.001) as a risk factor for Hb below the cutoff value. Analyzing the iron status abnormalities in an individual manner, ferritin <200 ng/dl was recognized as a risk factor (OR 1.96, CI 95% 1.41-2.72, p=0.001) and levels greater than 500 ng/dl (OR 0.53, CI 95% 0.35-0.79, p=0.002) were considered a protective factor, findings consistent with the current recommendations for iron supplementation in the KDIGO guidelines [22].

A systematic review and meta-analysis performed by Shepshelovich and cols. [28] which included 2369 patients with CKD in stages 3-5 and 818 patients with stage 5 CKD in dialysis treatment (5D) showed the superiority of IV iron use compared to oral iron supplementation to increase hemoglobin levels 1g/dl (RR 1.61, CI 95% 1.39-1.87 for CKD 3-5 and RR 2.12, CI 1.68-2,72 for CKD 5D) according to actual recommendations. In our study, 72.1% of patients had iron deficiency and just 12.4% were managed with IV iron, while 56.8% of patients received treatment with oral supplements. We did not find the variables related to iron metabolism as risk factors for Hb beneath the cutoff value.

The employment of ESA in the management of anemia in CKD patients increases the levels of Hb, diminishes transfusion requirements and decreases morbidity and mortality [29-33]. In our study, the EPO administration was considered a protective factor for Hb below the cutoff limit with an OR 0.57 (CI 95% 0.39-0.82, p=0.002) in the bivariate analysis and it remained as an independent factor after the multivariate analysis (OR 0.65, CI 95% 0.44-0.95, p=0.028).

In the studied population, we identified that 7.8% of the total patients with anemia were macrocytic anemias; however, a limitation of our results is we did not have routine determinations of folate or vitamin B12 levels. In other studies, macrocytic anemia due to folate or vitamin B12 deficiency is around 5% [7]. No benefit was found with folic acid administration (OR 1.10, CI 95% 0.78-1.54, p=0.572) or B-complex vitamins (OR 1.06, CI 95% 0.76-1.48, p=0.696).

Prescription of ACEI and ARB has been associated with anemia in CKD. A meta-analysis from Cheungpasitporn and cols [10] reported a RR of 1.57 (CI 95% 1.40-1.73, I2=17%) for ACEI and a RR of 1.58 (CI 95%, 1.38-1.83, I2=0%) for ARB use [13]. In our study, ACEI (OR 0.54, CI 95% 0.27-1.10, p=0.091) nor ARB (OR 1.03, CI 95% 0.76-1.39, p=0.84) were recognized as risk factors for Hb under the cutoff limit.

It has been previously described that women have lower levels of Hb and hematocrit than men. Physiological differences between genders participate in this variation. Considering different cutoff values to define anemia in each gender, the lower Hb levels in women are inferior to those in men at all CKD stages [34]. In this study we also encountered differences regarding a lower mean Hb in women (9.29 vs.10.01 g/dl); despite this, after conducting the multivariate analysis, the female gender was found to be a protective factor (OR 0.65, CI 95% 0.47-0-90, p=0.010) and, consequently, male gender a risk factor (OR 1.62, CI 95% 1.17-2.25, p=0.003) attributed to a better iron status and less mineral-bone metabolism disturbances in women.

Being retrospective, the study has several limitations, essentially due to the unavailability of laboratory tests of variables with known effect over the presence and severity of anemia such as PTH, vitamin B12 and folate values.

Conclusions

The prevalence of anemia in CKD patients receiving HD treatment at our setting is higher than what has been found in other populations. The modifiable causes associated to a lower concentration of Hb were disturbances in mineral-bone metabolism such as hyperphosphatemia and high calcium-phosphate product, as well as abnormalities in the variables related to iron metabolism and reduced usage of EPO. Periodic studies such the one presented here are necessary to detect improvement opportunities in the quality of care to decrease morbidity and mortality in HD patients.

Acknowledgments

We thank Dr. Jesús Manolo Ramos Gordillo and Dr. Félix Mark Olvera Cartas for the facilities provided to obtain the data for this study. A special thanks to Dr. Vilma Adriana Ajiz Payán for her unconditional support during the development of the study, writing and editing of the manuscript.

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