Erythropoietin in Cardiorenal Anemia Syndrome

Incidencies of heart and renal failure (HF, RF) together, are increasing in our country and all over the world, so a great attention has been dedicated to this problem recently. Th ese diseases together have shown bad results because of the process of accelerated arteriosclerosis, structural changes of myocardium, oxidative stress, infl ammation, increased activities of symphathetic nervous system (SNS), increased activities of a renin-angiotensin-aldosteron system (RAAS) (). Th ese factors are crucial in the development of patho-physiological process and consequential development of anemia, that together with heart and renal failure through interaction, cause serious disorder that we call the cardio-renal anemia syndrome (). We examined eff ects of erythropoietin (Epoetinum beta) at  ( men and  women) predialysed and dialysed patients with HF signs during a period of three years in individual dozes of - units subcutaneus (sc) weekly. Using computer S PLUS and SAS multiple variant analysis we have got correlations by Pearson. Epoetinum beta signifi cantly develops anemia parameters: number of erythrocytes (r=,; p<,), hemoglobin (r=,; p<,), MCV (r=,; p<,) at patients with HF. Positive eff ects are seen at NYHA class (r=,; p<,), on quality of life before and after prescribing medicine. Parameters of renal functions are improving: more urea (r =,; p<,) than creatinine (r=,; p<,) and potassium values K+) are not changed signifi cantly (r=,; p<,). Epoetinum beta has been useful in treatment of predialysed and dialysed patients with HF and anemia by improving functional ability of myocardium and quality of life.


Introduction
Erythropoietin (EPO) is represented as a hormone that is synthesized in the peritubular interstice of renal and it is main regulator of erythropoiesis.It is connected with specifi c receptors at the surface of hematopoietic cells, proerythroblast and it aff ects maturing of erythrocytes and hemoglobin synthesis.Erythropoietin production is regulated by negative reversed power through oxygen concentration in the blood.As a response on hypoxia, kidneys produce a large quantity of Erythropoietin and in that way contribute to increasing of the number of erythrocytes, and by that improve supplying oxygen to the tissue.Erythropoietin repre-sents protein of molecular weight of  daltons and made of  amino acids divided into three connected chains ().In  Amgen Laboratories and Fu-Kuen Lin cloned a gene for Erythropoietin, and  years later, in , recombinant human Erythropoietin (Rh-EPO) was synthesized and has been used in human medicine.Erythropoietin has non-erythropoietic eff ects that could be seen in a protective role at vascular diseases, lowering the zone of ischemia (for example at heart failure and cerebral vascular failure) protection of apoptosis through its antioxidant characteristics, and proangiogenic potential with positive remodeling of myocardium.Continuing researches of new medicines that will have better clinical results, Amgen researchers have developed a new type of Erythropoietin called Darboepoetin Alfa (ARANESP) which has a higher potential and its activities lasts longer compared with Rh-EPO and it is prescribed in intravenous (iv) or subcutaneous (sc) dozes of , micrograms/kg weekly ().Cardio-renal anemia syndrome was introduced in clinical practice by Silverberg with associates after he published the results of his study  ().He applied Erythropoietin in treatment of anemic patients with heart and renal failure with intravenous Ferum (Fe+) and managed to improve hemoglobin from , ± to ,±, during ,±, months and improving of EFLV, improving NYHA class and decrease of need for diuretics and hospitalizations.Anemia is often found in patients with chronic renal failure.By defi nition of WHO, anemia is characterized by decrease of hemoglobin (Hb)<gr/dcl (or , mmol/L) at women, and <gr/dl (or , mmol/ L) for men and women in postmenopausal phase.Anemia is seen at  patients whose creatinine clearance is <ml/min.Every decrease of hemoglobin for gr/dcl in chronic renal failure(CRF) causes dilatation of a left ventricle (LV) and creation or relapse of chronic heart failure (CHF).In the same time mortality is increased.Chronic anemia with increase of volume cause dilatation of heart cavity causing spreading of sarcomere and stronger myocardium contraction because of better folding of myofi lament (Starling's law).Because of increase of the volume LV walls become thicker and eccentric LV hypertrophy appears.Anemia, hypertension and diabetes mellitus are main independent predictors of hypertrophy LV in CRF ().Th e main patho-physiological mechanisms of anemia creation are decreased secretions of Erythropoietin in peritubular renal areas, negative eff ect of uremia toxins, appearance of hyperparatyreosis, increased blood loss through hemodialysis, appearance of hyperspleenism as a blood depot and places of fast wreck of erythrocytes, and toxic eff ects of aluminum that are applied in therapy at CRF patients (, ).On the other hand CHF development at anemic patients is followed by other patho-physiological mechanisms that are connected with tachycardia with increased heart volume and decrease of minute heart volume, venoconstriction, artery dilatation, dilatation and hypertrophic remodeling of LV.Apart from these mechanisms anemia creation in CHF is also infl uenced by medicines that are used frequently: aspirin, that additionally removes Ferum; ACE inhibitors that in CRF change renal production of erythropoietin; beta-blockers that slow transmission of prorenin into renin; anticoagulants and anti-aggregates that are frequently applied in CHF therapy and contribute anemia development by micro-bleedings into urinary and gastro tract (, ).In cardio-renal anemia syndrome due to signs of chronic infl ammation with malnutrition, increased secretion of cytokinin, of substances similar to tumor necrotized factor alpha and tumor necrotized factor alpha (TNF-α) that signifi cantly inhibit hematopoiesis, cause anemia and play important role at CHF (, , )

Materials and Methods
Eff ects of recombined Erythropoietin (rh-EPO) Epoetinum beta that has been given to pre-dialyzed and dialyzed patients have been examined.Dosage of Erythropoietin (rh-EPO) Epoetinum beta was from  to  I.U.sc - times a week depending of values of hemoglobin (Hb) ().Patients are observed during three years (-).In this study  patients were included:  men and  women from  municipalities of Hercegovina that belong to Clinical Hospital Mostar.Most of the patients were from Mostar (), Široki Brijeg (), Čapljina (), Jablanica (), Ljubuški (), Grude (), Čitluk (), Uskoplje (), Stolac (), Posušje (), Rama () and Neum ().All the patients had signs of chronic renal failure (CRF) from I-IV, signs of chronic heart failure (CHF) I-IV NYHA classifi cation and anemia signs by WHO criteria.In analysis of Erythropoietin effects (rh-EPO) Epoetinum beta, anemia parameters have been observed, renal and heart failure before and after therapy during three years.From anemia parameters number of erythrocytes/ L has been observed, hemoglobin gr/L, MCV; from renal function parameters we observed: urea/s, creatinine/s, glucose (GUK) and potassium/s (K + ); from parameters of heart failure we followed functional class by NYHA classifi cation.Statistical elaboration was done by using the S PLUS computer program for multi-variant data analysis and results are shown by table and graphics with correlation coeffi cient by Pearson and classical statistic method, arithmetic middle with minimal and maximal values and standard deviation (SD) (, , ).

Results
From  patients (predialysed and those on hemodialysis) aged -, arithmetic average of  years of age, standard deviation (SD)  years, had chronic renal and heart failure with emphasized anemia.Th e average number of erythrocytes was , x   /L at the beginning of the treatment with SD , and with range of ,-, x   L. Control measurement after observed period on an average was , x  /L with SD from , and range of ,-, x   /L.An average hemoglobin value (Hb) before start of the treatment was , gr/L with SD , gr/L and range from - gr/L; and after observatory period of three years an average value of hemoglobin (Hb) was , gr/L with SD , gr/L and range of - gr/L.An average value of MCV before the treatment was , ok/L with SD , and range of ,- and after the period of monitor-ing an average value was ,; SD , with range of ,-,.An average value of urea/serum before the treatment was , mmol/L with SD , and range of ,-,, and after the treatment an average value of urea was , mmol/L with SD , and range of ,-,.An average creatinum/serum value before the treatment was , μmol/L with SD , μmol/L and range of -.μmol/L and after the treatment an average value of creatinum was , μmol/L, SD was , mol/L with range of -.μmol/L.An average potassium (K+) value before the treatment was , mmol/L with SD , mmol/L and the range of ,-,mmol/ L ; an average K+ value after the treatment was , mmol/L, SD was , mmol/L with the range of ,-, mmol/L.An average NYHA class before the treatment was II and with range of I-IV; and after the treatment an average NYHA class was I with the range of I-II.By using multi-variant data analysis and statistical program S PLUS we have got correlation coeffi cients by Pearson that for the eff ect of Epoetinum beta on the number of erythrocytes was r=,; p<,; We also stress that four of our patients in observed period had signifi cant bleeding and one patient had developed infl ammation; on MCV r=,, p<,; the functional ability of myocardium by NYHA classification r=,, p<,.Th e results were shown graphically.

Discussion
Th e renal anemia at dialysed patients: Wizemann and associates () examined patients with CHD and concluded that Erythropoietin decrease ischemia caused by loading, and correction of the anemia decrease minute and heart volume and consuming of oxygen.Th at was confi rmed by our patients too.Besarab and associates (, ) found normal hematocrits at  ( patients) from which  ended terminally,  got nonfatal heart failure at study taken on  patients with evident angina pectoris and CHF signs at dialysed patients with CRF during  months observation.At  of the patients () with low hematocrits  ended terminally,  got nonfatal heart failure.Th ey have stressed that mortality decrease with increase of hematocrits in both groups of patients.
In our population we did not fi nd any fatal results during the observation period.Th e Australia study () found out that patients with high levels of hemoglobin show signifi cantly low dilatation LV, and incidence of hypertrophy LV was lowered at hemodialysed patients with CRF who was given rh-EPO.Th oraco-cardial measurements at our patients didn't show any signifi cant diff erences in the observation period.Canadian multi-centric study (, ) has shown that hemoglobin normalization at patients with cardiomyopathy causes decrease of concentric hypertrophy LV and its dilatation.Hayashi and associates () has examined eff ects of rh-EPO at predialysed patients and have shown that increase of hematocrites for more than  decrease in LV hypertrophy.At patients in the late CHF and CRF phase with hypertrophy or dilatation LV the eff ects of anemia correction are weaker, and that is also shown in our study.Th e rh-EPO treatment has good effect at preventing hypertrophy LV.Patients with advanced dilatation LV have weaker eff ect because of long term hypertrophy development and dilatation LV with structural abnormalities, and also weaker eff ects of rh-EPO.Al-Ahmad and associates () have shown that rise of mortality and morbidity because of heart diseases at patients with anemia, which is not the case in our study with our patients.Decrease of renal function and anemia as a risk factor increase mortality at patients with dysfunction LV.SOLVD study at  patients has shown that based on the multi-variant analysis of parameters of LV dysfunction on decrease of renal function and loss of hematocrits are risk factors for all causes of mortality.Loss of hematocrits for  together with increase of risk of . times for all causes of mortality (,,,).McClellan and associates () examined  patients with CHF and found out that hematocrits and creatinine are independently combined risk factors for mortality increase.Horwich and associates () examined anemia eff ect on mortality at  patients with CHF NYHA III-IV classifi cation and found out that anemia of the medium degree (Hb<, gr/dcl or , mmol/L) was observed with decrease of surviving and decline of the symptoms and functional status.Ezocowitz and associates () have found out that anemia is frequent in HF and combined with bad prognosis for the whole population of . patients with newly formed HF.Anemia is, at  of patients, independent prognostic marker for mortality.Silverberg and associates () have examined the role rh-EPO and usage of i.v Ferum (Fe+) at CHF patients with LVEF≤  and with Hb from - gr/dcl (,-, mmol/L).During , ±  months there was increase of hemoglobin ,-, gr/dcl (,-, mmol/L) and improving of NYHA class at  of patients ( had a decrease of NYHA class in the controlled group) and EFLV has increased for , in the treated group (it was decreased for , in the controlled group).Th e number of hospitalizations decreased for  which is in accordance with our observations.Cristina Opasich with associates () has stressed the need for establishing individual mechanisms of anemia creation in CHF in order to make better and right therapy by ferum, folic acid, B vitamins and Erythropoietin.

Conclusion
Erythropoietin significantly improves anemia parameters (erythrocytes, hemoglobin, MCV) at patients with HF.Positive effects were seen at renal function by decreasing urea more than creatinine.Epoetinum beta in our study does not show any significant effect of potasssium (K + ) values.The positive effects were seen on the LV function and improving the quality of life, especially at patients on hemodialisys.The functional ability of myocardium is improved for one to two classes of NYHA classification.Further studies of non-hematopoetic effects of Epoetinum beta, its effect on decrease of ischemia level, size of heart or brain failure, effect at endothelium remodeling and proangiogenic effects can be interesting for further studies and researches.