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The Relation of Erythropoietin Towards Homoglobin and Hematocrit in Varying Degrees of Renal Insufficiency

BaşlıkThe Relation of Erythropoietin Towards Homoglobin and Hematocrit in Varying Degrees of Renal Insufficiency
Publication TypeJournal Article
Year of Publication2015
AuthorsPanjeta, M, Tahirovic, I, Karamehic, J, Softic, E, Ridic, O, Coric, J
JournalMateria Socio Medica
Volume27
Issue3
Start Page144
Pagination144-148
Date Published06/2015
Type of ArticleOriginal
ISSN Number1986-597X (Online)
Abstract

Introduction: Hypoxia is a basic stimulant in production of erythropoietin (EPO). The primary function of erythrocytes is the transport of oxygen to tissues. Erythropoietin stimulates erythropoiesis which leads to increased production of erythrocytes- their total mass. This increases the capacity of the blood to carry oxygen, reduces the hypoxic stimulus and provides a negative feedback of stopping EPO production. The aim of this study was to establish a quantitative relationship between the concentration of erythropoietin, hemoglobin and hematocrit in different values of renal insufficiency. Material and methods: The survey was conducted on 562 subjects divided into two groups: with and without renal insufficiency. EPO, hemoglobin, hematocrit, serum creatinine and additional parameters iron, vitamin B12, and folic acid were determined by using immunochemical and spectrophotometric methods and glomerular filtration rate (GFR) was calculated as well. Results: EPO values (median) grow to the first degree of renal insufficiency, as compared to EPO values of healthy subjects, this increase is statistically significant, p=0.002. With further deterioration of renal function the values of EPO between all pathological groups are decreasing, and this decrease is statistically significant between first and second degree of renal insufficiency (RI) p<0.001. In the group of healthy subjects EPO is correlated rho = -0.532, p <0.0005 with hematocrit. The correlations are negative and strong and can be predicted by regression line (EP0 = 41.375- Hct * .649; EPO = 61.41–Hb * 0.355). In the group of subjects with the first degree of renal insufficiency EPO is in correlation with hematocrit rho=-0,574, p<0, 0005. It is also correlated with hemoglobin rho=-0.580, p< 0.0005. The correlation is negative (EP0= 42.168- Hct * 0.678). In the group of subjects with the third degree of renal insufficiency EPO is in correlation with hemoglobin rho=0.257, p=0.028. The correlation is medium strong and positive. In the group of subjects with third and fourth degree of renal insufficiency EPO is not in correlation with hemoglobin and hematocrit p>0.05. Conclusion: Renal dysfunction, depending on the level of RI effects differently on the biosynthesis of EPO in a diseased kidney, and consequently it also has a different effect on biosynthesis of HB in bone marrow and its content in the blood.

Full Text

Introduction:

Erythopoietin is a glycoprotein hormone composed of 165
amino acid residues with four complex carbohydrate chains attached
with peptide in the four binding positions (MW 30.4
kDa), and it has the role of the primary regulator of erythropoiesis.
EPO stimulates the proliferation and differentiation of
erythroid precursor cells in the bone marrow and in this way it
affects the production of red cells (1, 2).
Chronic renal insufficiency leads to hypo-regenerative anemia
due to the lack of erythropoietin. The level of synthesis
of EPO in the kidneys (or liver) is primarily governed by the
needs of the given cells for oxygen. Anemia is one of the most
common disorders in chronic renal insufficiency (3-7). Anemia
is diagnosed by measuring hemoglobin (Hb) levels (g / L) and
hematocrit (Hct) (percentage of red blood cells in the blood)
and by comparison with a given reference values. The most
important reason of anemia is the inability of the kidneys to
increase the synthesis of EPO in response to it (4. 8). For the
normal maturation of erythrocytes, except erythropoietin, it
is essential to have iron, folic acid and vitamin B12. Anemia is
an independent risk factor for development of cardiovascular
diseases in patients with chronic kidney disease. Large amount
of studies that were conducted show that every tenth person
in the world has a chronic kidney disease. Renal anemia is a
consequence of chronic kidney disease and occurs at an early
stage, it gets worse as the disease progresses (4, 5). With the fall
Mater Sociomed. 2015 Jun; 27(3): 144-148 • ORIGINAL PAPER 145
The Relation of Erythropoietin Towards Hemoglobin and Hematocrit in Varying Degrees of Renal Insufficiency
of the value of glomerular filtration rate the incidence of anemia
is increased. In studies of patients with chronic kidney disease
a direct correlation degree of anemia (concentration of Hb)
and renal failure (6) has been demonstrated. The treatment for
anemia with recombinant erythropoietin should be initiated on
the basis of glomerular filtration rate and hemoglobin, but it is
not enough clarified yet (7, 8). Apart from the mentioned facts,
anemia in kidney patients is not recognized and treated at the
right time; therefore this study has an aim to establish a quantitative
relationship between the concentration of erythropoietin,
hemoglobin and hematocrit in different values, glomerular filtration
rate, and to determine the legality of these connections.
2. MATERIAL AND METHODS
The survey was conducted on 562 subjects divided into two
groups with and without renal insufficiency. The subjects in the
group with RI are divided into 4 stages according to GFR rate:
first stage (60-89.99ml / min / 1.73m2) (25%), second stage
(30 to 59.99 ml / min / 1.73m2) 40%, third stage (15 to 29.99
ml / min / 1.73m2) and 20% of the fourth stage (14,99 ml
/ min / 1.73m2) 15% of the subjects. 365 (63%) subjects had
renal insufficiency (RI) (male 174 (49%) and female 182 (51%),
while 206 (37%) were with healthy kidney function (male 104
(51%) and female 102 (49 %) (19). The age structure of subjects
with RI is on average 59 ± 16 years, whereas control group
subjects are 49 ± 18 years. Additional parameters were set in
order to exclude other types of anemia caused by deficiency of
iron, vitamin B12 and folic acid. Humane samples were used
for these tests: serum and whole blood. The values of erythropoietin,
hemoglobin and hematocrit were determined. For
the determination of Hb concentration the counter of blood
elements was used (Cell Dyn 3700 system), which uses hemoglobin-
hydroxylamine colorimetric method. Hematocrit was
obtained by multiplying the volume of erythrocyte (MCV, mean
corpuscular volume) with the number of red blood cells. Creatinine
was determined by kinetic method based on Jaffe reaction
on auto analyzer Dimension RxL Siemens. Erythropoietin is
determined by enzymatic- chemiluminescent immunometric
method on IMMULITE / IMMULITE 1000 (Siemens) (11).
For each subject GF was calculated by using the calculator and
applying the MDRD formula (Modification of Diet in Renal
Disease). For the calculation we used the following variables:
age, sex, and serum creatinine (12).
For statistical analysis of the data obtained we used software
package SPSS for Windows (version 19.0, SPSS Inc., Chicago,
Illinois, USA) and Microsoft Excel (version 11th of Microsoft
Corporation, Redmond, WA, USA). For the connection and
direction of the connection between the variables we used the
correlation tests, depending on the type of variables (Spearman).
3. RESULTS
In the Table 1, values of EPO in subjects with first grade of
renal insufficiency are different in male and female population
and are statistically significant, p = 0.002.
EPO values were lower in men with average value of 12.25
mIU / mL, and a range (8.10 to 15.8 mIU / ml), than the value
of EPO in women with average value of 16,6 mIU / mL range
(13.4- 18.5 mIU / ml). Also, it was observed that with the weakening
of kidney function the gender differences in EPO values
is lost, p > 0.05. With the growth of the degree of renal insufficiency
EPO values (median) are decreasing, so the values of
EPO from the second to fourth degree of RI are not statistically
different between male and female subjects. Kruskal Wallis test
showed that there is a statistical difference in the average values
of EPO between certain categories of RI (in relation to the value
GF), p <0.0005. EPO values (medians) increase until the first
degree of renal failure, as compared to EPO values of healthy
subjects, this increase is statistically significant, p = 0.002.
In the group of healthy subjects (GF ≥90.0 ml / min / 1.73m2)
EPO is correlated rho = -0.532, p <0.0005 with hematocrit. The
correlation is strong and negative. With the fall of hematocrit
values of EPO increase. In the same group, EPO is correlated
with hemoglobin rho = -0.595, p <0.0005. The correlation is
strong and negative. Value of EPO increases with the decrease of
GF (ml/min/1,73m2)
Categories of RI Gender Number
of subjects
Percentage
(%) p (c2)
≥90,00
Male 104 50.5
0.899
Female 102 49.5
Total 206 100,0
60,00–89,99
Male 43 48.9
0.831
Female 45 51,1
Total 88 100.0
30,00–59,99
Male 67 47.5
0.556
Female 74 52,5
Total 141 100.0
15,00–29,99
Male 34 46.6
0.558
Female 39 53.4
Total 73 100,0
£ 14,99
Male 30 55.6
0.414
Female 24 44.4
Total 54 100.0
Table 1. Average values of EPO in all subjects, with and without renal
insufficiency, in relation to gender.
Level of RI
Glomerular filtration
(ml/min/1.73m2)
Spearman’’s
rho
Hematocrit
(%)
Hemoglobin
(g/L)
Healthy subjects
(≥90.00)
EPO
(mIU/mL)
Correlation
Coefficient -.532(**) -.595(**)
P .0005 .0005
N 206 206
1st degree
(60.00- 89.99)
EPO
(mIU/mL)
Correlation
Coefficient -.574(**) -.580(**)
P .0005 .0005
N 88 88
2nd degree
(30.00- 59.99)
EPO
(mIU/mL)
Correlation
Coefficient .083 .156
P .326 .065
N 141 141
3rd degree
(15.00- 29.99)
EPO
(mIU/mL)
Correlation
Coefficient .056 .257(*)
P .635 .028
N 73 73
4th degree
(≤14.99)
EPO
(mIU/mL)
Correlation
Coefficient .190 .208
P .169 .130
N 54 54
Table 2. Correlations of EPO, hematocrit and hemoglobin in relation to the
level of RI
ORIGINAL PAPER • Mater Sociomed. 2015 Jun; 27(3): 144-148
The Relation of Erythropoietin Towards Hemoglobin and Hematocrit in Varying Degrees of Renal Insufficiency
146
hemoglobin. In the group of subjects with the first grade of RI
(GF 60.00 to 89.99 ml / min / 1.73m2) EPO is correlated rho =
-0.574, p <0.0005 with hematocrit. The correlation is strong and
negative. The value of EPO increases with the decrease of hematocrit.
In the same group, EPO is correlated with hemoglobin rho
= -0.580, p <0.0005. The correlation is strong and negative. With
the fall of hemoglobin the value of EPO increases.
In the group of subjects with third grade of RI (GF 15.00-
29.99 ml / min / 1.73m2) EPO is correlated with hemoglobin
rho = 0.257, p = 0.028. The correlation is weak and positive.
Hemoglobin decreases with the decrease of EPO and vice versa.
In the group of patients with second and fourth degree of
renal insufficiency EPO is not correlated with hemoglobin and
hematocrit, p > 0.05.
Figure 1 shows that in healthy subjects with normal renal
function the values of EPO depend on hematocrit, R2 = 0.271,
p <0.0005. The dependence is linear, with the decrease of Pct
the value of EPO increases, the dependence can be represented
by linear regression equation: EP0 = 41,375- Hct * .649.
Regression analysis of patients with renal insufficiency
(60.00-89.99ml / min / 1.73m2) in figure 2 showed a correlation
between the levels of hematocrit and erythropoietin.
The dependence is linear and the value of EPO increases
with the decrease in hematocrit values, this can be represented
by linear regression equation: EP0 = 42,27- Hct * 0.68.
Regression analysis of healthy subjects in the figure 3 shows
the correlation between the level of hemoglobin and EPO.
The dependence is linear, EPO value increases with the
decrease in hemoglobin values, and this can be represented by
linear regression equation: EPO = 61.41–Hb * .355.
Regression analysis of patients with renal insufficiency
(60.00-89.00 ml / min / 1.73m2) in figure 3, showed a correlation
between the level of hemoglobin and erythropoietin.
The dependence is linear, EPO value increases with the de-
5
Histogram No.1. The values of the median and percentiles for all subjects grouped by level of RI
and healthy subjects
Kruskal Wallis test showed that there is a statistical difference in the average values of EPO
between certain categories of RI (in relation to the value GF), p <0.0005. EPO values (medians)
increase until the first degree of renal failure, as compared to EPO values of healthy subjects, this
increase is statistically significant, p = 0.002.
Table 2. Correlations of EPO, hematocrit and hemoglobin in relation to the level of RI
Level of RI
Glomerular filtration
(ml/min/1,73m2)
Spearman’'s rho Hematocrit
(%)
Hemoglobin
(g/L)
Healthy subjects
(≥90,00)
EPO
(mIU/mL)
Correlation
Coefficient -,532(**) -,595(**)
P ,0005 ,0005
N 206 206
1st degree
(60,00- 89,99)
EPO
(mIU/mL)
Correlation
Coefficient -,574(**) -,580(**)
P ,0005 ,0005
N 88 88
2nd degree
(30,00- 59,99)
EPO
(mIU/mL)
Correlation
Coefficient ,083 ,156
P ,326 ,065
N 141 141
3rd degree EPO Correlation ,056 ,257(*)
Pillars represent the median, and lines percentiles.
Healthy subj..
1st degree RI
2nd degree RI
3rd degree RI
4th degree RI
0,0
5,0
10,0
15,0
20,0
EPO (mIU/mL)
n=206
11,01
n=88
15,30
n=141
12,90
n=73
10,10
n=54
8,62





75 ti
25 ti
Histogram No.1. The values of the median and percentiles for all subjects
grouped by level of RI and healthy subjects
7
Figure 1 shows that in healthy subjects with normal renal function the values of EPO depend on
hematocrit, R2 = 0.271, p <0.0005.
Figure 1. Distribution of individual erythropoietin with linear regression analysis (glomerular
filtration ≥90ml / min / 1.73m2) with hematocrit (healthy subjects)
The dependence is linear, with the decrease of Pct the value of EPO increases, the dependence
can be represented by linear regression equation: EP0 = 41,375- Hct * .649.
25,00
20,0
15,0
10,0
5,0
30,0 35,0 40,0 45,0 50,0 55,0
Hematocrit (%)
Healthy subjects (GF ≥ 90,00 ml/min/1,73m2)
EPO (mIU/mL)
Figure 1. Distribution of individual erythropoietin with linear regression
analysis (glomerular filtration ≥90ml / min / 1.73m2) with hematocrit
(healthy subjects)
Regression analysis of patients with renal insufficiency (60.00-89,99ml / min / 1.73m2) in figure
2 showed a correlation between the levels of hematocrit and erythropoietin.
Figure 2. Distribution of individual erythropoietin levels and hematocrit with linear regression
analysis with glomerular filtration (60.00-89,99ml / min / 1.73m2)
The dependence is linear and the value of EPO increases with the decrease in hematocrit values,
this can be represented by linear regression equation: EP0 = 42,27- Hct * 0.68.
30,0
25,0
20,0
15,0
10,0
5,0
0,0
25,00 30,00 35,00 40,00 45,00 50,00 55,00
Hematocrit (%)
Glomerular filtration (60,00 - 89,99 ml/min/1,73m2 )
EPO (mIU/mL)
Figure 2. Distribution of individual erythropoietin levels and hematocrit
with linear regression analysis with glomerular filtration (60.00-89,99ml /
min / 1.73m2)
Regression analysis of healthy subjects in the figure 3 shows the correlation between the level hemoglobin and EPO.
Figure 3. Distribution of individual erythropoietin and hemoglobin levels with linear regression
analysis with glomerular filtration in healthy subjects (GF ≥ 90.00 ml / min / 1.73m2).
The dependence is linear, EPO value increases with the decrease in hemoglobin values, and can be represented by linear regression equation: EPO = 61.41 - Hb * .355.
25,0
20,0
15,0
10,0
5, 0
130,00 140,00 150,00 160,00 170,00 180,00
Hemoglobin (g/L)
Healthy subjects (GF ≥90,00 ml/min/1,73m2)
EPO (mIU/mL)
Figure 3. Distribution of individual erythropoietin and hemoglobin levels
with linear regression analysis with glomerular filtration in healthy subjects
(GF ≥ 90.00 ml / min / 1.73m2).
Mater Sociomed. 2015 Jun; 27(3): 144-148 • ORIGINAL PAPER 147
The Relation of Erythropoietin Towards Hemoglobin and Hematocrit in Varying Degrees of Renal Insufficiency
crease of hemoglobin values, and the dependence can be represented
by linear regression equation: EPO = 43,45- Hb * 0.21.
Figure 5 shows that the value of EPO depends on the values
of Hb in patients with the third degree of RI, R 2 = 0.099, p
= 0.007.
The dependence is linear, EPO value decreases with the decrease
of Hb values, and the dependence can be represented by
linear regression equation: EPO = 2.59 + 0.066 * Hb.
4. DISCUSSION
The importance as well as the frequency and severity of kidney
disease obliges professional national organizations to issue
recommendations for monitoring high-risk groups in order to
discover the renal impairment as soon as possible and to plan
a strategy for treating and monitoring of this disease, as well
as educating the population and medical workers. It is very
important to monitor the status and function of kidneys with
certain diagnostic tests because adequate and timely treatment
can significantly slow the progression of renal failure and substantially
preserve the function of kidneys (8, 10). Hyporegenrative
anemia is a common manifestation of chronic renal failure
and it is considered to be partly responsible for the symptoms
of chronic fatigue and poor general health condition associated
with chronic renal insufficiency. Timely detection of anemia
in kidney patients is very important, and the importance of
treating anemia is underlined as important fact in many recent
studies, and it would reduce deaths (6, 9). In healthy people relationship
between the mass of red blood cells and hemoglobin
saturation with oxygen is linear. In chronically anemic people
there is an inverse linear relationship between serum EPO and
hemoglobin (13, 14). In healthy people, exposure to high altitude
and consequent hypoxemia stimulates production of EPO (14,
15). Also, they speculate that this adjustment in the volume of
red blood cells is similar to adjustments of inhabitants of high
altitude to hypoxia (16). However, most authors report that
the increase in the mass of red blood cells is inappropriate with
regard to the degree of hypoxemia (17, 18).
Total amount of 562 subjects were included in this study,
and they were divided into two groups, with (356) and without
(206) renal insufficiency.
The level of erythropoietin is difficult to interpret in the
context of renal failure. Three studies examined the levels of
erythropoietin in relation to hemoglobin in patients with varying
degrees of renal insufficiency. Radtke and colleagues measured
EPO levels in 135 patients with renal failure (creatinine
clearance between 2 and 90 ml / min) and found significantly
increased average levels of EPO in all groups compared to the
average level of EPO for 59 reference subjects (CLcr> 90 mL
/ min). In patients with a creatinine clearance of <40 mL /
min, EPO levels were not adequate to provide the degree of
anemia. They found that levels of EPO are decreasing with
increased deterioration of excretory renal function. However,
the correlation between EPO and hemoglobin among various
groups has not been investigated in this study (20). Korte and
his associates have researched small groups of subjects (8 with
moderate renal insufficiency and 9 reference subjects) and they
found a significantly altered regulation (reduced secretion) of
EPO in patients with moderate renal insufficiency (21). Fehr
and colleagues measured EPO with 395 subjects and sought
correlations between groups with different renal impairment.
For subjects with creatinine clearance of <40 mL / min there
was no evidence of correlation between the levels of EPO and
hemoglobin compared to the reference group, and there was a
significant inverse correlation between the levels of EPO and
Hb in patients with a creatinine clearance above 40 mL / min
[EPO] (U / L) = 2.5 x (140 [Hb] (g / L)) or  [EPO] (U / L)
=–2.5 x  [Hb] (g / L); below this clearance level, no significant
correlation of EPO and hemoglobin was found (6). According
to these inquiries we got the following results.
The highest EPO values in comparison to healthy subjects are
in the first degree of RI, this difference is statistically significant
p=0.002. With further increase of renal insufficiency, value of
EPO decreases, between all categories of renal insufficiency,
and the decline is statistically significant between second and
third degree of renal insufficiency, p <0.0005. The correlation
searched for was between EPO, hematocrit and hemoglobin
depending on the level of RI. The correlation between EPO
and hematocrit was found in healthy subjects, EPO is correlated
10
Regression analysis of patients with renal insufficiency (60.00-89.00 ml / min / 1.73m2) in figure
3, showed a correlation between the level of hemoglobin and erythropoietin.
Figure 4. Distribution of individual erythropoietin and hemoglobin levels with linear regression
analysis with glomerular filtration (60.00-89.00 mL / min / 1.73m2)
The dependence is linear, EPO value increases with the decrease of hemoglobin values, and the
dependence can be represented by linear regression equation: EPO = 43,45- Hb * 0.21.
30,0
25,0
20,0
15,0
10,0
5,0
0,0
80,0 100,0 120,0 140,0 160,0 180,0
Hemoglobin (g/L)
1st degree of RI (GF 60,00 - 89,99 ml/min/1,73m2)
EPO (mIU/mL)
Figure 4. Distribution of individual erythropoietin and hemoglobin levels
with linear regression analysis with glomerular filtration (60.00-89.00 mL /
min / 1.73m2)
11
Figure 5 shows that the value of EPO depends on the values of Hb in patients with the third
degree of RI, R 2 = 0.099, p = 0.007.
Figure 5. Distribution of individual erythropoietin and hemoglobin levels with linear regression
analysis with glomerular filtration 15.00-29,99 ml / min / 1.73m2
The dependence is linear, EPO value decreases with the decrease of Hb values, and the
dependence can be represented by linear regression equation: EPO = 2.59 + 0.066 * Hb.
4. Discussion
The importance as well as the frequency and severity of kidney disease obliges professional
national organizations to issue recommendations for monitoring high-risk groups in order to
discover the renal impairment as soon as possible and to plan a strategy for treating and
monitoring of this disease, as well as educating the population and medical workers. It is very
important to monitor the status and function of kidneys with certain diagnostic tests because
adequate and timely treatment can significantly slow the progression of renal failure and
20,0
15,0
10,0
5,0
80,0 100,0 120,0 140,0 160,0 180,0
Hemoglobin (g/L)
EPO (mIU/mL) 3rd level RI (GF15,00-29,99 ml/min/1,73m2))
Figure 5. Distribution of individual erythropoietin and hemoglobin levels
with linear regression analysis with glomerular filtration 15.00-29,99 ml /
min / 1.73m2
ORIGINAL PAPER • Mater Sociomed. 2015 Jun; 27(3): 144-148
The Relation of Erythropoietin Towards Hemoglobin and Hematocrit in Varying Degrees of Renal Insufficiency
148
rho = -0.532, p <0.0005 with hematocrit. The correlation is
strong and negative. The value of EPO increases with the decrease
of hematocrit. In referent group, EPO is in correlation
with hemoglobin. The correlation is strong and negative. The
value of EPO increases with the decrease of hemoglobin. With
regression analysis of healthy subjects, correlations are presented
with linear regression equation: EPO = 61.41–Hb * .355; EP0
= 41,37- Hct * 0.65. The research on healthy subjects did not
show a statistically significant effect of glomerular filtration rate
on EPO value, p> 0,05. In the group of patients with the first
grade of renal insufficiency EPO is correlated rho = -0.574, p
<0.0005 with hematocrit. The correlation is strong and negative.
The value of EPO increases with the decrease of hematocrit.
In the same group, EPO is correlated with hemoglobin rho =
-0.580, p <0.0005. The correlation is strong and negative. The
value of EPO increases with the decrease of hemoglobin and
this can be represented by linear regression equation: EPO =
43,45- Hb * .213. EPO is not correlated with hemoglobin and
hematocrit (p> 0.05) in patients with second grade of RI. In
patients with the third grade of renal insufficiency EPO is correlated
with hemoglobin rho = 0.257, p = 0.028. The correlation
is weak and positive. Regression analysis showed a linear
dependence in the third degree of RI. Value of EPO decreases
with the decrease of hemoglobin and this dependence can be
represented by linear regression equation: EPO = 2,59+ Hb *
.066. In the fourth degree of renal insufficiency EPO is not correlated
with GF, hemoglobin or hematocrit, p> .05. Our results
indicate that the reduced levels of erythropoietin synthesis are
observed below GF (30ml / min / 1.73m2). Overall, the study
showed that the evaluation of the regulation of erythropoietin
occurs differently for different level of RI.
5. CONCLUSIONS
Renal dysfunction, depending on the level of RI responds
differently to the biosynthesis of EPO in a diseased kidney,
and consequently, it differently affects the biosynthesis of hemoglobin
in the bone marrow and its contents in whole blood.
CONFLICT OF INTEREST: NONE DECLARED.
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