|Year : 2020 | Volume
| Issue : 1 | Page : 105-109
Predictors of erythropoietin hyporesponsiveness in chronic hemodialysis patients
Ahmed Rabea, Ahmed Ragheb, Mahmoud Emara, Ahmed M Kamal
Department of Internal Medicine, Faculty of Medicine, Menoufia University, Shebin El-Kom, Egypt
|Date of Submission||10-Feb-2019|
|Date of Decision||27-Feb-2019|
|Date of Acceptance||02-Mar-2019|
|Date of Web Publication||25-Mar-2020|
Ahmed M Kamal
17 El-Sayed Gomaa Street, El Bagour
Source of Support: None, Conflict of Interest: None
The aim of this work was to assess different clinical and laboratory parameters to predict erythropoietin hyporesponsiveness in chronic hemodialysis patients with anemia.
Anemia resistant to erythropoietin-stimulating agents (ESAs) is a risk factor for all-cause mortality. Determining the etiologies of hyporesponsiveness may help to overcome the resistance.
Patients and methods
This cross-sectional study was carried out on 97 chronic hemodialysis patients attending Menoufia University Hospital and Manshiet Sultan hemodialysis units. Patients were classified according to the presence of anemia (hemoglobin < 10 g/dl) and ESA hyporesponsiveness index more than or equal to 10 into four groups: group I comprised nonanemic and ESA-responsive patients, group II comprised nonanemic and ESA-hyporesponsive patients, group III comprised anemic and ESA-responsive patients, and group IV comprised anemic and ESA-hyporesponsive patients. We compared groups I and IV with respect to influential factors.
The proportion of patients treated with renin-angiotensin-aldosterone system blockers (RAAS blockers) was significantly higher in group IV compared with group I (P = 0.000). Group IV patients had significantly lower dialysis adequacy (Kt/V) (P = 0.029) and significantly higher platelet to lymphocyte ratio (PLR), C-reactive protein (CRP), and intact parathormone hormone (P = 0.002, 0.000, and 0.006, respectively). There were significant positive correlations between mean ESA hyporesponsiveness index and CRP, PLR, and intact parathormone hormone and negative correlation with Kt/V. In multivariate analysis, treatment with RAAS blockers, inflammatory markers (PLR and CRP), and secondary hyperparathyroidism were independent predictors of ESA resistance.
RAAS blockers' treatment, inflammation, and secondary hyperparathyroidism could be considered as predictors of ESA hyporesponsiveness.
Keywords: anemia, erythropoietin-stimulating agents hyporesponsiveness, erythropoietin-stimulating agents hyporesponsiveness index, hemodialysis
|How to cite this article:|
Rabea A, Ragheb A, Emara M, Kamal AM. Predictors of erythropoietin hyporesponsiveness in chronic hemodialysis patients. Menoufia Med J 2020;33:105-9
|How to cite this URL:|
Rabea A, Ragheb A, Emara M, Kamal AM. Predictors of erythropoietin hyporesponsiveness in chronic hemodialysis patients. Menoufia Med J [serial online] 2020 [cited 2020 Jun 6];33:105-9. Available from: http://www.mmj.eg.net/text.asp?2020/33/1/105/281310
| Introduction|| |
Anemia is one of the most common complications of end-stage renal disease (ESRD). About 90% of patients have anemia, which is associated with increased cardiovascular and all-cause mortality, and diminished quality of life and exercise tolerance,.
With the advent of erythropoietin-stimulating agents (ESAs), there has been a significant improvement in the side effects of anemia and the need for blood transfusion. However, a substantial number of ESRD patients have reduced response to ESAs. ESA hyporesponsiveness is defined as failure to reach the recommended target hemoglobin (Hb) despite high doses of ESA or requiring high doses to maintain the target Hb. ESA hyporesponsiveness has a negative impact on dialysis patients' survival.
Various factors have been associated with ESA hyporesponsiveness in different studies, such as iron deficiency, secondary hyperparathyroidism, inadequate dialysis, inflammation, malnutrition, and drugs such as renin-angiotensin-aldosterone system blockers (RAAS blockers),.
Thus far, different definitions and indices have been proposed for ESA hyporesponsiveness. The kidney disease outcomes quality initiative guidelines describe ESA hyporesponsiveness as a continued need for greater than 300 IU/kg per week Erythropoietin (EPO) subcutaneously. As Hb response is not included in this definition, various studies assessed ESA hyporesponsiveness by using ESA hyporesponsiveness index (EHRI). EHRI is calculated by dividing weekly ESA dose per kilogram of body weight (IU/kg/W) by Hb level (g/dl). EHRI is an easily calculated index that has direct relation with mortality in dialysis patients,.
We conducted this study to determine the risk factors of ESA hyporesponsiveness among hemodialysis patients.
| Patients and Methods|| |
This cross-sectional study was approved by the ethical committee of Faculty of Medicine, Menoufia University, and the patient gave an informed consent. The study was carried out on 97 ESRD patients maintained on regular hemodialysis attending Menoufia University Hospital and Manshiet Sultan hemodialysis units during the period spanning from December 2017 to December 2018.
Patients older than 18 years of age undergoing hemodialysis for at least 6 months before the study were enrolled. Those with a history of hematologic disorders such as thalassemia, sickle cell disease, myelodysplastic syndrome, and hematologic and solid organ active malignancies were excluded.
Patients were classified according to the presence of anemia (Hb <10 g/dl) and EHRI more than or equal to 10 into four groups: group I comprised nonanemic and ESA-responsive patients (n = 41), group II comprised nonanemic and ESA-hyporesponsive patients (n = 4), group III comprised anemic and ESA-responsive patients (n = 29), and group IV comprised anemic and ESA-hyporesponsive patients (n = 23). In the current work, in order to study the factors affecting the pathogenesis of anemia and ESA hyporesponsiveness, we limited the comparisons to group I (frank ESA responders with Hb ≥ 10 and EHRI < 10) and group IV (frank ESA-resistant patients with Hb < 10 and EHRI ≥ 10). As regards groups II and III, they could not be categorized as either frank responders or frank resistant patients to ESA therapy (group II was considered ESA responsive but needed high doses of ESA so that their EHRI was >10, and group III was not considered ESA resistant, as with the trials to increase ESA dose, they may have responded and reached the target Hb) so that both groups were excluded from the statistical analysis.
Demographic data, dialysis vintage, dose of ESAs (unit/week), and RAAS blockers treatment during the period of the study were recorded. Clinical examination was carried out with special emphasis on mean arterial pressure and BMI that was calculated as body weight (kg) divided by height (kg/m2). Three consecutive monthly laboratory records of patients were collected, and data were entered into specifically designed software. Laboratory data included complete blood picture analyzed in an automated ADVIA-120 hematological analyzer (Siemens Healthcare, Erlangen, Germany), data on mineral bone disease [corrected serum calcium, phosphorus, intact parathormone hormone (intact PTH), and serum albumin] analyzed in AU480 BECK Man USA analyzer (Atlantic Lab Services, Delray Beach, Florida, USA), iron status (serum iron, total iron-binding capacity, ferritin) analyzed in the Automated AAII-25 Colorimetric (CDC, Atlanta, Gorgia, USA), renal function tests (blood urea, serum creatinine) analyzed in Integra 400 Autoanalyzer (Roche Diagnostics, Mannheim, Germany), dialysis adequacy (sp Kt/V) by using the classic Daugirdas equation, 12-lead ECG to exclude ischemic heart disease, and inflammation [C-reactive protein (CRP)] by Turbidimetry.
We used mean Hb level and erythropoietin dose during the 3-month period of evaluation for calculating EHRI. EHRI was calculated by dividing weekly ESA dose per kilogram of body weight (IU/Kg/W) by Hb level (g/dl),.
Demographic, clinical, and laboratory data of the cases were tabulated.
Data entry, coding, and analysis were conducted using SPSS (22) (IBM Corp. Released 2013, IBM SPSS Statistics for Windows, version 22.0;IBM Corp., Armonk, New York, USA). Description of quantitative variables was in the form of mean and SD, description of qualitative variables was by frequency and percentage, χ2 test was used to assess the relationship between two qualitative groups, and t test was used to assess the relationship between two quantitative groups. P value less than or equal to 0.05 was set to be statistically significant.
| Results|| |
There were no significant differences in age, sex, smoking, and dialysis vintage between groups I and IV [Table 1].
There was no statistically significant difference between the studied groups with regard to the clinical data (BMI and mean arterial pressure) and also with regard to the comorbidities (diabetes mellitus, hypertension, cardiovascular disease, and hepatitis C virus infection). A significantly higher proportion of patients in group IV were using RAAS blockers compared with those in group I (P = 0.000) [Table 2].
|Table 2: Comorbidities, renin-angiotensin-aldosterone system blocker history, and clinical data of the studied groups|
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In the view of dialysis adequacy, there was a significant decrease in the mean Kt/V in group IV (1.1 ± 0.1) versus (1.2 ± 0.1) that in group I (P = 0.029). The incidence of inflammation [as evaluated by CRP and platelet to lymphocyte ratio (PLR)] was significantly increased in group IV, with mean CRP 43 ± 25.3 versus 22.1 ± 17.9 in group I and mean PLR 119.2 ± 31.1 versus 95.8 ± 26.3 in group I (P = 0.000 and 0.002, respectively). The incidence of secondary hyperparathyroidism was significantly increased in group IV, with mean intact PTH 872.1 ± 336.6 versus 577.7 ± 420.7 in group I (P = 0.006) [Table 3].
There were significant positive correlations between mean EHRI and CRP, PLR, and intact PTH and negative correlation with Kt/V. In multivariate analysis, treatment with RAAS blockers, inflammatory markers (PLR and CRP), and secondary hyperparathyroidism were independent predictors of ESA resistance [Table 4].
|Table 4: Multivariate logistic regression analysis of ESA hyporesponsiveness index|
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| Discussion|| |
The results of our study are summarized as follows: 52 (53%) patients were anemic (Hb < 10 g/dl) in comparison with Kaze et al. study, a cohort study involving 95 hemodialysis patients, with 75 (79%) patients having anemia.
Patients' mean Hb level was 10.1 ± 1.2 g/dl, although about 29% of the studied cohort had a Hb level below the recommended target of 10 g/dl, despite prescription of ESAs. Thus, we evaluated ESA hyporesponsiveness using ERHI.
Different studies have addressed the risk factors of ESA hyporesponsiveness, although the results are contradictory. The most mentioned risk factors were absolute or functional iron deficiency, blood loss, inflammation, inadequate dialysis, diabetes, hyperparathyroidism, and RAAS blockers.
In the comparison of groups IV and I, there were no age or sex or dialysis vintage differences. We found no statistical difference between the studied groups with regard to nutritional status (BMI and serum albumin), in contrast to the study by Samavat and colleagues, which proved lower BMI and serum albumin as risk factors of hyporesponsiveness and, also, in contrast to the study by Afsar, which revealed that the ERI score was correlated negatively with albumin (r = −0.270, P = 0.011). This could be explained by the presence of protein-energy malnutrition. Indeed, a large proportion of dialysis patients have wasting and low serum albumin, which are predictors of the response to EPO. Hypoalbuminemia could be the result of malnutrition or inflammation among their patients,.
Interestingly, treatment with RAAS blockers was significantly more common among group IV patients (78.3 vs. 26.8%, P < 0.000), who performed one-way Dunn's ANOVA test, univariate and multivariate analyses on 100 patients to determine any significant improvement in erythropoiesis among studied groups. Confirming that the Angiotensin converting enzyme (ACE) inhibitors/Angiotensin Receptor Blockers (ARBs) inhibit erythropoiesis induced by Recombinant Human Erythropoietin (rHuEPO) in ESRD patients; therefore, simultaneous use of ACE inhibitors/ARBs and rHuEPO should be carried out with caution. Inhibition of renin angiotensin system inhibits erythropoiesis by decreasing angiotensin II availability, which is a growth factor for erythrocytes. Moreover, RAAS blockers can lead to an elevated level of negative regulator of erythropoiesis of acetyl-seryl-aspartyl-lysyl-proline (AcSDKP),.
With respect to dialysis adequacy, there was a significant decrease in the mean Kt/V in group IV (1.1 ± 0.1 vs. 1.2 ± 0.1, P = 0.029), which is in agreement with Alves and colleagues, showing that patients with adequate dialysis assessed by Kt/ V require lower doses of rHuEPO. However, this is in contrast to the study by Samavat and colleagues, which surprisingly was having Kt/V above 1.4. The inadequacy in dialysis dose is an important cause of anemia due to the presence of uremic toxins, which inhibit the production of EPO and erythropoiesis. Furthermore, the dialysis procedure causes mechanical damage to erythrocytes and leads to blood loss,.
In order to evaluate the effect of inflammation on ESA response, we used CRP, and PLR as a marker of inflammation; there was a significant difference between the studied groups, with mean CRP in group IV being 43 ± 25.3 versus 22.1 ± 17.9 in group I and mean PLR being 119.2 ± 31.1 versus 95.8 ± 26.3 in group I (P = 0.000 and 0.002, respectively); this is in agreement with the study by Taymez and colleagues, which was the first literature to show the relationship between PLR and ERI (r = 0.227, P = 0.021), and, in contrast to the study by Samavat and colleagues, which had no difference between the studied groups with regard to inflammation. Inhibition of erythropoiesis by cytokines, such as tumor necrosis factor-alpha and interferon-gamma, are important for erythropoietin resistance,.
Serum PTH level was significantly different between groups I and IV (872.1 ± 336.6 vs. 577.7 ± 420.7, P = 0.006). This is in agreement with the study by Alves and colleagues. As bone marrow fibrosis due to hyperparathyroidism is known as the cause of ESA resistance, better control of phosphate level and hyperparathyroidism among both groups omitted the predictive property of intact PTH.
However, after multivariate logistic regression analysis, treatment with RAAS blockers, inflammation, and intact PTH remained significantly different among the studied groups.
Our study had limitations; the cross-sectional design of the study made it difficult to drive a solid cause and effect relationship. A prospectively designed study would help define a model for prediction of response to ESAs.
| Conclusion|| |
Apart from the most validated parameters responsible for ESA hyporesponsiveness (e.g., iron deficiency, dialysis inadequacy, and poorly controlled serum phosphate level), other potential risk factors such as treatment with RAAS blockers, inflammation, and secondary hyperparathyroidism should be evaluated to overcome ESA resistance.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
El Sewefy D, Farweez B, Behairy M, Yassin N. Impact of serum hepcidin and inflammatory markers on resistance to erythropoiesis-stimulating therapy in hemodialysis patients. Int Urol Nephrol 2019; 51
Chen L, Ling YS, Lin CH, He JX, Guan TJ. High dose ESAs are associated with high i.PTH levels in hemodialysis patients with end-stage kidney disease: a retrospective analysis. Front Public Health 2015; 3
Drozdz M, Weigert A, Silva F, Frazão J, Alsuwaida A, Krishnan M, Jacobson S. Achievement of renal anemia KDIGO targets by two different clinical strategies–a European hemodialysis multicenter analysis. BMC Nephrol 2019; 20
Bamgbola O. Resistance to erythropoietin-stimulating agents: etiology, evaluation, and therapeutic considerations. Pediatr Nephron 2012; 27
Ogawa T, Shimizu H, Kyono A, Sato M, Yamashita T, Otsuka K,et al
. Relationship between responsiveness to erythropoiesis-stimulating agent and long-term outcomes in chronic hemodialysis patients: a single-center cohort study. Int Urol Nephrol 2014; 46
Hejaili F, Hafeez E, Bhutto B, Al Turki L, Alsuwida A, Raza H, Al-Sayyari A. Variables affecting darbopoetin resistance index in hemodialysis patients. Saudi J Kidney Dis Transpl 2017; 28
Gilbertson DT, Peng Y, Arneson TJ, Dunning S, Collins AJ. Comparison of methodologies to define hemodialysis patient's hyporesponsive to epoetin and impact on counts and characteristics. BMC Nephrol 2013; 14
Kaze F, Meto D, Halle M, Ngogang J, Kengne A. Prevalence and determinants of chronic kidney disease in rural and urban Cameroonians: a cross-sectional study. BMC Nephrol 2015; 16
KDIGO. KDIGO clinical practice guideline for anemia in chronic kidney disease. Kidney Int 2012; 2
Alves MT, Vilaca SS, Carvalho M, Fernandes AP, Dusse LM, Gomes KB. Resistance of dialyzed patients to erythropoietin. Rev Bras Hematol Hemoter 2015; 37
Samavat S, Nafar M, Khoshdel A, Alipour-Abedi B. Factors contributing to erythropoietin hyporesponsiveness among hemodialysis patients: a cross-sectional multicenter study. Nephrourol Monthly 2017; 9
Afsar B. The relationship between depressive symptoms and erythropoietin resistance in stable hemodialysis patients with adequate iron stores. Int J Artif Organs 2013; 5
Qureshi I, Abid K, Ambreen F, Qureshi A. Angiotensin converting enzyme inhibitors impair recombinant human erythropoietin induced erythropoiesis in patients with chronic renal failure. Saudi Med J 2007; 28
Elbasheer Z, Ahmed I, Edriss A, Ms B, Elmusharaf K, Banaga A. Failure of response to erythropoietin in end stage renal disease patients undergoing hemodialysis. Sudan Med J 2018; 54
Weiss G, Ganz T, Goodnough L. Anemia of inflammation. Blood 2019; 133
Taymez D, Ucar E, Turkmen K, Ucar R, Afsar B, Gaipov A, Turk S. The predictive value of platelet/lymphocyte ratio in hemodialysis patients with erythropoietin resistance. Ther Apher Dial 2016; 20
Kim I, Kim J, Kim M, Lee D, Hwang C, Han M, Lee S. Low 1, 25-dihydroxyvitamin D level is associated with erythropoietin deficiency and endogenous erythropoietin resistance in patients with chronic kidney disease. Int Urol Nephrol 2018; 50
[Table 1], [Table 2], [Table 3], [Table 4]