ASSOCIATION BETWEEN THE POLYMORPHISM OF ANGIOTENSIN-CONVERTING ENZYME GENE AND INTERLEUKIN-1 BETA GENE AND THE RESPONSE TO ERYTHROPOIETIN THERAPY IN DIALYSIS PATIENTS WITH ANEMIA
Dzekova-Vidimliski P, Eftimovska-Otovikj N, Nikolov I G, Selim Gj, Rambabova-Bushljetik I, Pushevski V, Karanfilovski V, Matevska-Geshovska N, Dimovski A
*Corresponding Author: Assoc. Prof. Pavlina Dzekova-Vidimliski, MD, PhD, University Hospital for Nephrology, Mother Theresa str 17, 1000 Skopje, R. North Macedonia, Email address: pavlinadzekova@yahoo.com
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DISCUSSION
The study included patients with stage 5 chronic
kidney disease on dialysis with anemia treated with re-
combinant human erythropoietin. The mean hemoglobin
level of 109.4 ± 11.1 g/l was achieved in study patients
with an average dose of erythropoietin of 6909 IU per
week. The target value of hemoglobin in dialysis patients
is 110-120 g/l (8,9). The mean level of TSAI (%) in the
study patients was 29.4 ± 7.6%, and the mean level of
ferritin was 468.8 ± 343.1 µg/l. KDIGO (Kidney Disease:
Improving Global Outcomes) guidelines for anemia in
chronic kidney disease recommend not exceeding a TSAI
of 30% and a serum ferritin level of 800 ng/ml (20).
The mean value of iPTH in study patients was 499.3 ±
490.3 pg/ml. KDIGO guidelines recommended main-
taining iPTH levels 2- to 9-fold the upper normal limit, corresponding to a range of 130–600 pg/mL (21). The
mean value of the ERI was 9.6 ± 6.2 IU/kg/week/g/dl.
In the study of Santos EJF et al. with a total number of
99 patients with anemia treated with erythropoietin, the
mean value of ERI was 15.3 ± 9.0 IU/kg/week/g/dl (23).
The mean ERI value of 7.0 ± 4.4 IU/kg/week/g/dl was
noted in 60 patients on peritoneal dialysis in the study
performed by Kaneko S et al. (24).
A hemoglobin level above 110 g/l with erythropoi-
etin therapy was achieved in 53.6% of the study patients.
Patients with hemoglobin ≥ 110 g/l were characterized by
significantly higher serum values of albumin, cholesterol,
and iron compared to patients with hemoglobin <110 g/l.
The serum values of CRP, weekly dose of rHuEPO, and
ERI were significantly higher in patients with hemoglobin
< 110g/l, compared to patients with hemoglobin ≥ 110g/l.
Malnutrition and inflammation in dialysis patients were
associated with anemia and resistance to erythropoietin
therapy (25, 26). Radić J et al. studied 101 patients on
peritoneal dialysis, divided into two groups, a group of
60 patients (59.4%) with hemoglobin ≥ 110 g/l and a
group of 41 patients (40.6%) with hemoglobin<110 g/l.
The serum value of the albumin was significantly higher
in the group of patients with the level of hemoglobin ≥
110 g/l compared to the group of patients with the level
of hemoglobin <110 g/l, (44.2 ± 8.5 vs. 39.9 ± 8.5, P =
0.003). Also, the serum value of CRP was significantly
higher in the group with hemoglobin <110 g/l compared
to the group with hemoglobin ≥ 110 g/l, (7.8 ± 7.9 vs. 3.5
± 6.3, P = 0.005) (26).
Patients involved in the study with an ERI ≥10 IU/kg/
week/g/dl had significantly lower serum values of iron and
TSAI% and significantly higher serum values of ferritin and
CRP compared to patients with an ERI <10 IU/kg/g/dl. Iron
deficiency and inflammation were the most common causes
of reduced erythropoietin response during the treatment
of anemia in dialysis patients (27). Ferritin and CRP are
well-known acute-phase proteins of inflammation (28,29).
The frequency of polymorphism of the ACE I/D gene
in the study patients was: 14,5% with ACE II, 59,4% with
ACE I/D, and 26,1% with ACE DD. A study by Jeong KH
et al. included 167 patients on hemodialysis, with a similar
frequency of polymorphism of the ACE I/D gene: 25.1%
with ACE II, 54.5% with ACE I/D, and 20.4% with ACE
DD (19). The frequency of polymorphism of the IL-1B
C/T gene in the study patients was 10.1% with IL-1B CC,
50.7% with IL-1B CT, and 39.1% with IL-1B TT. The
distributions of IL-1B C/T polymorphism in the study
of Jeong KH and al. with 167 hemodialysis patients was
21.6% with IL-1B CC, 43.1% with IL-1B CT, and 35.3%
with IL-1B TT (19). In the same study, the ACE DD and
IL-1B CC genotypes were associated with significantly
lower values of ERI compared to other genotypes (ACE II:
13.2 ± 5.5 vs. ACE I/D: 13.9 ± 7.6 vs. ACE DD: 10.0 ± 5.1,
P = 0.038, and IL-1B CC: 9.6 ± 5.1 vs. IL-1B CT: 15.2 ±
7.5 vs. IL-1B TT: 12.2 ± 5.7, P = 0.004) (19). The associa-
tion of ACE DD with lower ERI value was also confirmed
in a group of 50 patients with chronic kidney disease and
anemia in a study by Nand N et al. (13). The same study
did not confirm the association of polymorphism of the
IL-1b gene with ERI (13). A study by Varagunam M et al.
included 46 patients on peritoneal dialysis with anemia,
treated with erythropoietin, and showed that genotype
ACE DD was associated with lower total weekly doses of
erythropoietin compared to genotypes ACE II and ACE I/D
(22). Kiss Z et al. evaluated 660 hemodialysis patients with
anemia treated with erythropoietin and the patients with
ACE DD genotype had significantly higher ERI compared
to the patients with ACE II (P = 0.046) (30). In our study,
there was no significant association of polymorphism of
the ACE and IL-1b genes with rHuEPO responsiveness
in dialysis patients. Several published studies did not find
a significant association between genetic polymorphism
and erythropoietin treatment response in dialysis patients.
The pro-inflammatory cytokine polymorphism was not as-
sociated with rHuEPO responsiveness in a study with 112
patients on peritoneal dialysis (12). Hatano M et al. did not
find a significant association between the ACE polymor-
phism and the rHuEPO dose in 91 hemodialysis patients
(31). The polymorphism of the ACE was genotyped in 70
Iraqi patients on hemodialysis and there was no significant
effect of polymorphism on hemoglobin levels (32).
Our study has several limitations: the small sample
size, no measurement of serum angiotensin II levels, and
erythropoietin levels in studied patients, which might be
a possible explanation for rHuEPO responsiveness. Many
other ACE gene polymorphism could affect the response
to rHuEPO as rs4343, rs429, and rs4341, which may be in
linkage disequilibrium with studied rs1799752.
In conclusion: iron deficiency, inflammation, mal-
nutrition, and hyperparathyroidism are factors associated
with anemia and resistance to erythropoietin therapy in
dialysis patients. The genetic polymorphism have been
identified as possible causes of resistance to erythropoi-
etin in dialysis patients. Studies with a larger sample size
should be performed to confirm the association of poly-
morphism with erythropoietin responsiveness.
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