Mini ReviewAbstract
Nowadays over million of patients with terminal kidney insufficiency are treated with some of the methods of the kidney function replacement. Appearance of the human recombinant Erythropoietin EPO approved by U.S. Food Administration 1989 , is one of the most significant progress in treating patients. Three of the pathophysiological processes are involved in the appearance of anemia in the chronic kidney insufficiency : insufficient production of erythropoetin and decreased response of stem cells of the erythrocytopoiesis in the bone marrow to action of Erythropoietin (EPO): inhibition of the bone marrow with toxic meatabolites that are not eliminated from the body due to disturbed excretory kidney function; uremic toxins acts as inhibitors of heme synthesis but may have an ihibitory effect to erythroid stem cell differentiation. The aim of this work was to show the role of Erythropoietin to the patients on hemodialysis.
Keywords: Anemia; Dialysis; Erythropoietin
Abbreviations: ERA: European Renal Association; EDTA: European Dialysis and Trasplant Association; NKF: National foundation for kidney; EBPG :European Best Practice Guideline; DOQI: Dialysis Outcomes quality Initiative
Mini Review
Terminal kidney insufficiency is a condition of irreversible
loss of kidney parenchyma what have for a consequence loss
of kidney function. Before the replecement methods had been
introducted (hemodialysis, peritoneal dialysis) patients with
terminal insufficiency died [1,2]. Methods for kidney function
replacement (RRT) are peritoneal dialysis and hemodialysis and
kidney transplantation [3,4]. Hemodialysis is a method for kidney
fuction replacement where blood is taking out extracorporeally.
Taking the blood out of the body over acute blood vessels, two
volume venous catheters or over punction of main blood vessels
(AV fistula, AV graft) to the dialyzer membrane is reached by
use of highly sofisticated machines. Dialyzer (membrane) is an
artifical kidney which imitates glomerular basement membrane
with selective permeability. Exchange of matter is performed
through semipermeable membrane by simultan use of basic
physical processes diffusion and osmossis . During process of the
hemodialysis constant flow of the blood performs on one side of
the membrane and from the other side dialyze liquid which has
plasma like balance. However the basic bicarbonate hemodialysis
that corrects the acidosis to the patient with 8,4 % of bicarbonate
as well as derived modality HDF (hemodiafiltration) that allows
depuration by ultrafiltration processes is still very far from the
possibility of replacing the real kidney function. Diffusion and
filtration processes provide controlled exchange of disolved
substances and water , remove some substances from the blood
(urea, creatinine, natrium, water) and substitute necessary ones
from the dialyse liquid (bicarbonate, calcium, magnesium) [5,6].
In this way it is posibble more or less successfuly to replace (the
excretory elimination of final products of protein decomposition,
drugs) and partly regulatory function of the kidneys (composition
and volume of extracellular fluid) while endocrine and metabolic
function are day by day successfuly modulated and replaced
by drugs (Erythropoietin, modulation of plasmarenin activity,
influence on prostaglandin generation, substitution of active
vitamine D3). Treating of the patients with hemodialysis in
European countries started at the end of 50’s and beginning of 60’s and doctors who started application of these methods found
in 1964 Association for dialysis and transplant (European Dialysis
and Trasplant Association- EDTA ) [7] AND Europen Register got
the name ERA – EDTA (European Renal Association) [8]. Treatment
by hemodialysis in Montenegro started on 18 June in 1979 in the
Centre for hemodialysis in Podgorica and from 1989 exsist seven
centers where around 170 patients have a treatment and every
year around 50 new patients demand tretment by hemodialysis.
By hemodialysis provides better life quality of these patients [9].
National foundation for kidney in The USA (NKF) I EBPG (European
Best Practice Guideline ) published a couple of the recomendations
, such as recomendation for adequacy of hemodialysis (dose of
hemodialysis) [10]. Measurement of the realised hemodialysis
dose is usualy counted by counting of the index Kt/ W. Kt/V what
is a measure of plasma amount purified from urea , divided with
volume of distribution for urea. It is widely accepted attitude that
the patien is properly dialised when Kt /V is between 1,2 i 1,5 .
Anemia
In patients with chronic kidney insufficiency , normocytic and
normochromic anemia are regulary present what singnificantly
contributes to the symptomatology of chronic kidney failure. It is
usually observed when JGF value falls between 30ml / min and
creatinine rises to about 265um / l. The hematrocrit progressively
decreases below 15-20 % in the absence of bleeding. The severity
of anemia usually corresponds to the degree of azotemia. When
anemia to the patients with chronic kidney insufficiency is not
treated properly it includes a wide range of psyhological disorders
that include decreased tissue oxygenation, decreased delivery
of oxygen to the tissues and their utilization. Erythropoiesis
is supressed by the effects of retained toxins on erythrocytes ,
reducing biosynthesis of erythropoietin in diseased kidneys such
as with the presence of circulating inhibitors of erythropoiesis
[11,12]. Many factors contributing to anemia [13] and they are
hypersplenism, gastrointestinal bleeding, chronic blood loss during
hemodialysis , anticoagulant therapy also during hemodialysis
and toxic effects of aluminium. Anemia in a state of chronic kidney
insufficiency is caused by three pathophysiological mechanisms
, insufficient production of erythropoietin, reduced response of
selected erythrocytopoiesis stemm cells in the bone marrow to
the action of erythropoietin (EPO); inhibition of bone marrow
by toxic metabolits that are not eliminated from the body due to
imparied excretory kidney function, uremic toxins act as inhibitors
of heme syntesis but may have an inhibitory effect on erythroid
stem cell differentiation. It is considered that pharathormone
,which is secreted in chronic kidney insufficiency is one of the
inhibitors of erythrocytopoiesis , the shortened life of erythrocytes
ia a consequence of metabolic products that act as extracorpuscular
hemolytic factors.
The development of anemia leeds to attempts of involving
compensatory mechanisms such as increased erythropoiesis but
this is impossible due to lack of EPO producing cells, increased
ventilation but shortness of breath because of the saturation
of the respiratory system , acceleration of circulation which
includes increased possibility for a stoke and cardiac output.
Clinical manifestation of anemia are [13] : weakness, intermittent
claudication , heart failure and sometimes angina pectoris. The
clinical picture is dominated by various symptoms and signs of
kidney insufficiency while palor of the skin and visible mucous
membranes indicate anemia. The diagnosis of anemia is set by
examination of the peripheral blood and bone marrow with signs
of the presence of chronic kidney or renal failure. Peripheral
blood anemia is normocytic and normochromic , there is rarely
macrocytosis or hypochromia and microcytosis, reticulocyte
count is normal or slightly reduced, platelet function is imparied,
which causes a tendency to bleed, in the peripheral blood smear
erythrocytes are observed , bone marrpw cellularity is usually
normal , which is in relation to the degree of anemia as a pathological
finding where erythroid hyperplasia would be expected.
In treatment good results are achieved by application of
recombinant human Erythropoietin [14] which is efficent and well
tolerated in attempt to achieve and sustain concetration of Hb with
it from 100 -120 g/l. When the target concretation is reached the
dose of EPO should be reduced [4,15-17]. Kidney transplatation
represents one succesful way of anemia treatment in chronical
kidney insufficiency [4]. Multucentric studies show results of the
therapy with Erythropoietin in anemia suppression to the patients
with chronic kidney failure. Improving that Erythropoietin is the
most significant factor for anemia [18-21]. The basic reason of
anemia to the patients with chronic kidney failure is insufficient
production of Erythropoietin in the kidneys [22]. Erythropoietin is
a hormone , sialoglycoprilen , essential for the final differentation
of stem cells of erythropotesis. It is synthesised mostly in kidneys
, ports in circulation and in the serum of the health patients there
is 20mm/ml. Synthesis of EPO is regulated by the mechanism of
negative feedback and it depends of it how the tissues are supplied
by the oxygen. Beside kidneys in EPO synthesis are partly involved
extrarenal sources, the most probably liver in which Epo is formed
exclusively in the fetus. In an adult a kidney is an organ in which
EPO is already formed and the liver is responsible for synthesis
around 20 % of EPO while hypoxia stimulies synthesis of EPO
but not already synthesised EPO which is deposited in the kidney.
EPO is produced by highly differented cells of connective tissue,
fibrolasts placed in the renal cortex between renal tubula. In these
cells there isn’t depo of Erythropoietin because the whole amount
is delivered after the synthesis.
The strongest stimuli of EPO synhesis is hipoxia. It brings to the
production of EPO- MRNA in the mentioned cells. It is considered
that a definite role in this process belongs to the renal tibula. During
the process of fibrosis development due to renal failure it appears
massive fibroblast proliferation in the renal cortex. Progressive loss of tibula cause loss of links between EPO productive cells and
tubula that surroundes them. Fibroblast changes their phenotype
and became miofibroblast and loose ability of production EPO. As a
consequence of that appears sharp fall of EPO in the blood. Before
1989 characteristic lack of Erythropoietin in renal failure could be
treated only with blood transfusion and anabolic stereoids with
limited success and following complications. Appearance of the
recombinant human Erythropoietin , EPO improved by US Food and
Drug Administration in 1989 is one of the most significant progress
in the treatment of kidney patients in the last decade. Studies which
follow the level of mortality and hospitalization support criteria of
National Kidney Foundation Dialysis Outcomes quality Initiative
(DOQI) that hematocrit in range from 33 to 36 % provides the best
following effects [23].
EPO could be given intravenously or subcutaneously. The most of the studies show that application of EPO subcutaneously has saving effects [24,25] where optinal value of hematocrit is achieved with smaller losts EPO [20]. There are studies which talk about advantages of subcutaneously implementation of Erythropoietin [26-30] in the therapy of anemia to these patients in relation to venous application and they are lower doses and level of pain and costs of the treatment. Efficiency of EPO therapy depends of adequate dose, frequency and application. It is common to be given a dose of 20-50Iu / kg TM three times a week and then if a target hematocrit isn’t reached to increase dose to 25-96% every fourth week [31]. If it is necessary to apply bigger dose than 150 UI /kg three times a wekk than it is considered that exsists resistency to EPO. Therapy guideline : Supression of anemia in HBI by giving of Erythropoietin Sc 80-120J /kg a week (is divided in 2-3 doses a week) IV -120- 180J/kg a week (divided into 3 doses a week ) target Hct / Hb 33-36 % , 11-12g/dl optimal way of correction. Increasment of Hct for 4-6 % during 4 weeks (achievement of target value inside 2-3 months period). Ocassional single values of hemoglobin that are above or under wished ones could be noticed to the patients because of the variability. Variability of hemoglobin should be treated throuh adoption of the dose of target range of 10g/dl (6,2mml) up to 12g/ dl (7.5mmol/l )[32,33]. Keeping the level of hemoglobin above 12g/dl (7.5mmol/l ) should be avoided. If the speed of hemoglobin rise is bigger than 2g/dl (1.25mmol/l ) during one month or it rises to 12g/dl (7.45mmol/l )a dose should be lower for 25%. If the level of hemoglobin continues to rise therapy should be stopped until its level starts to fall and then begin the therapy again in a dose for 25 % lower than the previous one. Patients condition should be followed carefully to provide application of the lowest dose of Eritropoetin that provides adequate control of anemia symtoms. If the hypertension is present or some other cardiovascular or cerebrovascular disesase or disease of the periferal blood vessels level of the Hb should be decided according to the health condition of the patient.
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