Anemia is common in patients with chronic kidney disease (CKD) and contributes to cardiovascular alterations. Recent findings suggest that B-type natriuretic peptide (BNP) is a sensitive biomarker for left ventricular dysfunction, but relationship between hemoglobin and BNP in CKD patients is unclear. Hemoglobin, plasma BNP and serum creatinine levels were measured in 49 patients with CKD (without heart failure), divided in two groups according to the hemoglobin status (cut-off point 110 g/L). All patients underwent echocardiography in order to assess left ventricular (LV) morphology and function. The results showed that in the group of patients with hemoglobin levels under 110 g/L BNP levels were significantly elevated (p<0.001), as well as left ventricular mass index (p<0.001). Systolic and diastolic LV function were significantly better in patients with hemoglobin levels above 110 g/L (p<0.001). Hemoglobin levels were inversely related to BNP values (r=–0.451, p<0.001). Significantly negative correlation between BNP level and creatinine clearance (p=0.009), and significantly positive correlation between BNP level and left ventricular mass index (LVMI) were established. A similar but positive relationship was observed between hemoglobin levels and creatinine clearance (p<0.01). We established statistically significant negative correlation between hemoglobin levels and LVMI (r=–0.564, p<0.001). In conclusion, BNP and hemoglobin levels depend on the renal function. Anemia may contribute to elevated BNP levels in CKD patients, and may represent an important confounder of the relationship between BNP and cardiac alteration in these patients

Almira Hadžović-Džuvo

Monika Tomić

Senija Rašić

Slavica Ćorić

Snježana Unčanin

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Coll. Antropol. 33 (2009) Suppl. 2: 141–144Original scientific paperImpact of Hemoglobin Concentration on PlasmaB-type Natriuretic Peptid Level and Left VentricleEchocardiographics Characteristics in ChronicKidney Disease PatientsSenija Ra{i}1, Almira Had`ovi}-D`uvo2, Monika Tomi}3, Snje`ana Un~anin1 and Slavica ]ori}31 Clinic of Nephrology, University Clinical Center Sarajevo, Sarajevo, Bosnia and Herzegovina2 Institute of Physiology and Biochemistry, School of Medicine, Sarajevo, Bosnia and Herzegovina3 Clinic of Internal Medicine, University Clinical Hospital Mostar, Mostar, Bosnia and HerzegovinaA B S T R A C TAnemia is common in patients with chronic kidney disease (CKD) and contributes to cardiovascular alterations. Re-cent findings suggest that B-type natriuretic peptide (BNP) is a sensitive biomarker for left ventricular dysfunction, butrelationship between hemoglobin and BNP in CKD patients is unclear. Hemoglobin, plasma BNP and serum creatininelevels were measured in 49 patients with CKD (without heart failure), divided in two groups according to the hemoglobinstatus (cut-off point 110 g/L). All patients underwent echocardiography in order to assess left ventricular (LV) morphol-ogy and function. The results showed that in the group of patients with hemoglobin levels under 110 g/L BNP levels weresignificantly elevated (p<0.001), as well as left ventricular mass index (p<0.001). Systolic and diastolic LV functionwere significantly better in patients with hemoglobin levels above 110 g/L (p<0.001). Hemoglobin levels were inverselyrelated to BNP values (r=–0.451, p<0.001). Significantly negative correlation between BNP level and creatinine clear-ance (p=0.009), and significantly positive correlation between BNP level and left ventricular mass index (LVMI) were es-tablished. A similar but positive relationship was observed between hemoglobin levels and creatinine clearance (p<0.01).We established statistically significant negative correlation between hemoglobin levels and LVMI (r=–0.564, p<0.001).In conclusion, BNP and hemoglobin levels depend on the renal function. Anemia may contribute to elevated BNP levelsin CKD patients, and may represent an important confounder of the relationship between BNP and cardiac alteration inthese patients.Key words: hemoglobin, B-type natriuretic peptide, left ventricle, chronic kidney diseaseIntroductionCardiovascular diseases are the leading cause of mor-bidity and mortality in patients with chronic kidneydisease1. Left ventricular hypertrophy (LVH) is frequen-tly observed cardiac alteration in these patients2. Patho-genesis of LVH in patients with chronic kidney disease ismultifactorial and includes systolic hypertension, ane-mia, older age life, etc. Anemia is a basic characteristic ofchronic kidney disease, and pathogenetically besidesother factors includes the deficit of erythropoietin, ab-breviated life of erythrocytes, the deficit of nutritionalfactors and disturbance of iron metabolism. In a state ofrelative tissue hypoxia, anemia causes peripheral vasodi-latation as a compensatory response, and the peripheralvasodilatation and decrease of the blood viscosity result-ing in an increased vein inflow as well as an increase incardiac output. Cardiac output increases to meet meta-bolic needs and leads to the remodeling of left ventricle3.Studies so far have indicated that B-type natriuretic pep-tide (BNP) is a sensitive biomarker of left ventricularhypertrophy4,5, and that anemia can have a significantimpact on the concentration of B-type natriuretic pep-tide (BNP) in the plasma6.141Received for publication March 13, 2009The aim of this study was to determine the relation-ship between the concentration of hemoglobin in theblood and the concentration of BNP in plasma, and theirimpact on geometry of the left ventricle in patients withchronic kidney disease.Patients and MethodsPatientsThe study included 49 patients (19 men and 30 wo-men) with chronic kidney disease (creatinine clearance<60 mL/min), without the need for renal replacementtherapy. All patients were divided into two groups basedon their hemoglobin status: the group with hemoglobinconcentration lower than 110 g/L and the group with he-moglobin concentration higher than 110 g/L. The studywas conducted at the Clinic of Nephrology, UniversityClinical Center in Sarajevo, during the period from Sep-tember 2006 to December 2008. The study did not in-clude patients with coronary heart disease, congenitalheart malformations or heart failure.MethodsEchocardiograph examination was carried out usingultrasonic recorder Toshiba SSH 140 with 2.5 MHz trans-ducer and the cardiologist who was not familiar with theclinical patient data. Measurements of left ventricularposterior wall thickness (PWd), interventricular septalwall thickness (IVSd) and left ventricular internal diam-eter (LVIED) were made from long-axis parasternal posi-tion at the end of diastole. Left ventricular (LV) mass wascalculated according to Devereux modified formula of theAmerican Society of Echocardiography, and LV mass in-dex was derived by dividing LV mass to body surfacearea. LVH was defined as the left ventricular mass index(LVMI) >131 g/m2 for men and >100 g/m2 for women inaccordance with Framingham criteria7. Echocardiogra-phic measurements in all patients were performed on theday when the blood sample was taken to measure thelevel of BNP.Level of plasma B-type natriuretic peptide was mea-sured by the technique of enzymatic immunoassay usingcommercial kit assays AxSYM BNP on appliance AxSYMAbbott. Levels of BNP up to 100 pg/mL were consideredas normal values. Concentration of hemoglobin in theblood and serum concentration of creatinine were deter-mined by the routine laboratory methods. All measure-ments were performed at the Institute for Clinical Bio-chemistry at the University Clinical Center Sarajevo, thesame day when the blood sample was taken. The level ofcreatinine clearance (mL/min) was calculated by usingthe Cockroft-Gault formula: (140-age) ´ body weight (kg)/0.81 ´ serum creatinine (ìmol/L), whose result for femalepersons is multiplied with the constant 0.85.StatisticsStatistical analysis was performed using SPSS soft-ware (version 16). Data were expressed as means andstandard deviation (SD) for normally distributed variab-les and as median with interquartile ranges for non-nor-mally distributed data. Comparations between groupswere made by Student’s t-test and Mann-Whitney U test,for normally and non-normally distributed date. Coeffi-cient of correlation was assessed by Spearman. We as-sumed a statistical significance for p<0.05.ResultsFrom a total of 49 observed patients with chronic kid-ney disease, 26 patients had blood level of hemoglobin be-low 110 g/L (average value 91.5 g/L) and 23 patientsabove 110 g/L (128.8 g/L). Demographic, laboratory andechocardiographic characteristics of patients per groupare shown in Table 1. Between the tested groups therewere no significant differences in age.Average value of B-type natriuretic peptide concen-tration in the group of patients with severe renal anemia(Hgb<110 g/L) was significantly higher compared to thegroup of patients with a hemoglobin level above 110 g/L(median 922.6 pg/mL vs. 103.4 pg/mL, p<0.001, Figure1). Value of creatinine clearance, expressed in mL/min,was significantly lower in the group of patients with agreater degree of renal anemia (33.8 mL/min vs. 62.7mL/min, p<0.001).Echocardiographic analysis indicates that LV mass in-dex is significantly higher in renal patients with more pro-nounced anemia and lower creatinine clearance (p<0.001).Patients with hemoglobin levels higher than 110 g/Lhave a significantly better systolic (EF 57.2% vs. 54.2%,p<0.001) and diastolic LV function (E/A 0.90 vs. 0.75,p<0.001).The inverse relationship of BNP concentration andthe hemoglobin level of statistical significance in ob-S. Ra{i} et al.: Hemoglobin, BNP and Left Ventricle in Kidney Disease, Coll. Antropol. 33 (2009) Suppl. 2: 141–144142TABLE 1CHARACTERISTICS OF THE CKD PATIENTSBY HEMOGLOBIN STATUSGROUP 1(hemoglobin<110 g/L)GROUP 2(hemoglobin>110 g/L)N 26 23Age (years) 52.2±3.5 55.6±2.3Hemoglobin (g/L) 91.5±2.4 128.8±2.5*BNP (pg/ml)922.6[492.5–2066.7]103.4*[42.2–430.3]Creatinine clearance(ml/min)33.8±2.4 62.7±7.9*IMLV (g/m2) 185.4±8.05 141.4±8.3*EF (%) 54.2±2.3 57.2±1.2*E/A 0.75±0.03 0.90±0.05*Results are presented as mean ± standard deviation or as me-dian with interquartile range* p<0.05 in comparation with group 1(patients with hemoglobinstatus <110 g/L)served patients with chronic kidney disease was showed(r=–0.451, p<0.001, Figure 2).Significant negative relationship between level of he-moglobin and LV mass index, as well as significant posi-tive relationship between level of BNP and LV mass in-dex were demonstrated (Table 2).At the same time creatinine clearance, as an indicatorof endogenous renal function, shows a significant posi-tive correlation with the hemoglobin value, and the in-verse correlation with the BNP concentration. The levelof BNP in plasma is shown as a negative indicator of sys-tolic and diastolic LV function, while the hemoglobin is inpositive correlation with ejection fraction of LV and withthe parameter of diastolic LV function, E/A.DiscussionAnemia associated with chronic kidney disease is de-fined with low hemoglobin values and accompanied withsignificant cardiovascular morbidity. Mechanisms of car-diovascular adjustment to anemia are reflected in the in-creasing cardiac output, initiated by the decrease of vas-cular peripheral resistance and increase of the heart rateand left ventricular contractility due to increase in con-centration of catecholamines and non-catecholaminesinotropic factors and chemoreceptor stimulation by hy-poxia and increase in sympathetic nerve activity3,8.The results of our study clearly confirm the relation-ship between the degree of anemia and degree of kidneydysfunction, and the size of LV mass index. Patients withhemoglobin levels below 110 g/L have a significantlygreater LV mass index and significantly poorer systolicand diastolic LV function.At the same time it has been confirmed that renal pa-tients with lower hemoglobin values have significantlyhigher values of BNP concentration. Identified signifi-cant negative correlation between hemoglobin status andBNP concentration in monitored patients, as well as be-tween the level of creatinine clearance and BNP concen-tration, indicates that higher BNP concentrations, asanemia, may be the result of renal impairment.This study has also confirmed significantly higherBNP concentrations in patients with more pronouncedLV hypertrophy, and significant positive correlation ofBNP levels with the LV mass index. This observationmay reflect increased production of BNP in associationwith left ventricular hypertrophy. BNP is a polypeptidewhich is being synthesized as a preproBNP in the ventri-cular myocardium and enzymatically cleaved into proBNP.Prohormone (proBNP) is under the action of enzymesfrom the group of proteases cleaved to the biologically ac-tive form of BNP and amino terminal portion of pro-hormone – NTproBNP. Active hormone BNP is being ex-creted in ventricles in response to myocite stretching andis therefore believed to be a more sensitive indicator ofthe ventricular structure from other natriuretic peptides.Vasodilatation and hemodynamic alteration in renalanemia contribute to an increase in venous blood returnS. Ra{i} et al.: Hemoglobin, BNP and Left Ventricle in Kidney Disease, Coll. Antropol. 33 (2009) Suppl. 2: 141–144143Hb<110 g/L Hb>110 g/L0,001000,002000,003000,00BNP(pg/ml)Fig. 1. Plasma BNP concentration in CKD patients by hemoglo-bin status. Bars indicate maximum and minimum value, whilethe square and its central bar are showing the intequartile rangeand median.60,00 80,00 100,00 120,00 140,00 160,00Hb (g/L)0,001000,002000,003000,004000,005000,00BNP(pg/ml)r=-0.451, p<0.001Fig. 2. Relationship between BNP and hemoglobin concentrationsin CKD patients.TABLE 2CORRELATION BETWEEN HEMOGLOBIN AND BNP STATUSWITH ESTIMATED PARAMETERS IN ALL PATIENTS WITH CKDLV massindexCreatinineclearanceEF E/AHemoglobin r=–0.564p<0.001r=0.594p<0.01r=0.148p=0.319r=0.335p=0.02BNP r=0.617p<0.001r=–0.569p=0.009r=–0.059p=0.692r=–0.319p=0.029to the heart and the gradual development of LVH. Leftventricular hypertrophy is eccentric, characterized by in-crease of LV internal diameter and normal attitude of thewall thickness toward diameter of the cavity, as it occursin other forms of load volume. It is known that LV massincreases with kidney disease progression9. Expansion ofthe ventricular wall in response to volume expansion andincrease of pressure in the ventricle, together with neuro-humoral stimulation, induces BNP secretion. Signifi-cantly higher values of BNP in renal patients with grea-ter LV mass index, and significantly positive correlationbetween BNP levels and LV mass index, as well as signifi-cantly negative correlation of BNP values with diastolicfunction of hypertrophic myocardium indicates that theBNP is a sensitive indicator of ventricular structure andfunction.Significantly higher levels of BNP in the presence ofthe higher level of kidney failure could be the result ofcombining renal failure and the presence of cardiac dis-ease, respectively LV hypertrophy. Mark et al.10 showedthat the level of BNP depends on renal and cardiac dys-function, as well as numerous factors associated with theprogression of kidney diseases, including the anemia andLVH. Study by Knudsen et al.6 suggests that anemia maycontribute to the increase of BNP level in the absence ofheart failure, and that anemia contributes significantlyto the relation between BNP concentrations and cardiacfunction, as well as prognosis.In conclusion, results of our study indicate that thelevels of hemoglobin and the levels of BNP depend onrenal function, but also there is causal relation betweenanemia, levels of BNP and cardiac alterations, such asLV hypertrophy in chronic kidney disease. Anemia maycontribute to elevated BNP levels in CKD patients, andmay represent an important confounder of the relation-ship between BNP and cardiac alteration in these pa-tients.R E F E R E N C E S1. CULLETON BF, LARSON MG, WILSON PW, EVANS JC, PAR-FREY PS, LEVY D, Kindey Int, 56 (1999) 2214. — 2. LEVIN A, SINGERJ, THOMPSON CR, ROSS H, LEWIS M, Am J Kidney Dis, 27 (1996) 347.— 3. METIVIER F, MARCHAIS SJ, GUERIN AP, PANNIER B, LONDONGM, Nephrol Dial Transplant, 15 Suppl 3 (2000) 14. — 4. UUSIMAA P,TOKOLA H, YLITALO A, VUOLTEENAHO O, RUSKOAHO H, RISTE-LI J, LINNALUOTO M, PEUHKURINEN K, Int J Cardiol, 97 (2004)251. — 5. KHAN IA, FINK J, NASS C, CHEN H, CHRISTENSON R,DEFILIPPI CR, Am J Cardiol, 97 (2006) 1530. — 6. WOLD KNUDSENC, VIK-MO H, OMLAND T, Clinical Science, 109 (2005) 69. — 7. LEVY D,SAVAGE DD, GARRISON RJ, ANDERSON KM, KANNEL WB, CASTE-LLI WP, Am J Cardiol, 59 (1987) 956. — 8. ECKARDT KU, Nephrol DialTransplant,14 (1999) 1317. — 9. STEWART GA, GANSEVOORT RT,MARK PA, Kidney Int, 67 (2004) 217. — 10. MARK PA, STEWART GA,GANSEVOORT RT, PETRIC CJ, MCDONAGH TA, DARGIC HJ, ROD-GER RSC, JARDINE AG, Nephrol Dial Transplant, 21 (2006) 402.S. Ra{i}Clinic of Nephrology, University Clinical Center Sarajevo, Bolni~ka 25, 71000 Sarajevo, Bosna i Hercegovinae-mail: rasicnef@bih.net.baUTJECAJ KONCENTRACIJE HEMOGLOBINA NA RAZINU NATRIURETSKOG PEPTIDA TIPA BI EHOKARDIOGRAFSKE KARAKTERISTIKE LIJEVE SR^ANE KLIJETKE U BOLESNIKA SAKRONI^NOM BUBRE@NOM BOLESTIS A @ E T A KAnemija je ~esto prisutna u bolesnika sa kroni~nom bubre`nom bolesti (KBB) i doprinosi pojavi kardiovaskularnihpromjena. Noviji nalazi sugeriraju da je natriuretski peptid tipa B (BNP) senzitivan biomarker disfunkcije lijeve sr~aneklijetke, ali je odnos izme|u hemoglobina i BNP-a u bolesnika sa KBB jo{ nejasan. Razine hemoglobina, plazmatskogBNP-a i serumskog kreatinina su mjerene u 49 bolesnika sa KBB (kreatinin klirens <60 mL/min), razdijeljene u dvijegrupe prema statusu hemoglobina (to~ka razdvajanja 110 g/L). Svim pacijentima je ura|ena ehokardiografija u ciljuutvr|ivanja morfologije i funkcije lijeve sr~ane klijetke (LK). Rezultati pokazuju da su u grupi bolesnika sa razinomhemoglobina iznad 110 g/L, razine BNP-a bile signifikantno pove}ane (p<0,001), kao i indeks mase lijeve klijetke(p<0,001). Sistolna i dijastolna funkcija LK su bile signifikantno bolje u bolesnika sa razinom hemoglobina iznad 110g/L (p<0,001). Razine hemoglobina su u inverznom odnosu sa razinom BNP-a (r=–0,451, p<0,001). Utvr|ena je signi-fikantna negativna korelacija izme|u razine BNP-a i kreatinin klirensa (p=0,009), te signifikantna pozitivna korelacijaizme|u razine BNP-a i indeksa mase lijeve klijetke (IMLK). Sli~an, ali pozitivan odnos je uo~en izme|u razina hemoglo-bina i kreatinin klirensa (p<0,01). Utvrdili smo statisti~ki signifikantnu negativnu korelaciju izme|u razina hemoglo-bina i IMLK (r =–0,564, p<0,001). U zaklju~ku, razine BNP-a i hemoglobina su ovisne od bubre`ne funkcije. Anemijamo`e doprinositi pove}anju razina BNP-a u bolesnika sa KBB, te mo`e predstavljati zna~ajan ~imbenik odnosa izme|uBNP-a i sr~anih promjena u ovih bolesnika.S. Ra{i} et al.: Hemoglobin, BNP and Left Ventricle in Kidney Disease, Coll. Antropol. 33 (2009) Suppl. 2: 141–144144

Impact of Hemoglobin Concentration on Plasma B-type Natriuretic Peptid Level and Left Ventricle Echocardiographics Characteristics in Chronic Kidney Disease Patients

Impact of Hemoglobin Concentration on Plasma B-type Natriuretic Peptid Level and Left Ventricle Echocardiographics Characteristics in Chronic Kidney Disease Patients

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