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In clinical practice, renal dysfunction is common and associated with re-hospitalization and reduced survival in patients with heart failure. Objectives: To determine the prevalence, characteristics of renal function in heart failure patients and to investigate the relationship between reduced renal function with the degree of heart failure, left ventricular ejection fraction, serum BNP.
Journal of military pharmaco-medicine no5-2018 RENAL DYSFUNCTION IN HEART FAILURE PAITIENTS Nguyen Duy Toan*; Le Thi Ngoc Han* Tran Duc Hung *; Nguyen Oanh Oanh* SUMMARY Background: In clinical practice, renal dysfunction is common and associated with re-hospitalization and reduced survival in patients with heart failure Objectives: To determine the prevalence, characteristics of renal function in heart failure patients and to investigate the relationship between reduced renal function with the degree of heart failure, left ventricular ejection fraction, serum BNP Methods and results: In 95 patients with heart failure at Department of Cardiology, 103 Military Hospital from 2016 November to 2017 April, 52.6% of the patients had worsening renal function Mean NYHA functional class was 3.34 ± 0.63 for -1 -2 -1 -2 eGFR < 60 mL.min 1.73m higher than 3.06 ± 0.69 for eGFR ≥ 60 mL.min 1.73m (p < 0.05) There was a significant correlation between eGFR and left ventricular ejection fraction with r = 0.54 (p < 0.001) There was a reversal correlation between eGFR and serum BNP level with r = -0.25 (p < 0.01) Conclusions: The more severe HF was, the less eGFR was Estimated GFR correlated positively with left ventricular ejection fraction and negatively with BNP concentration in patients with HF * Keywords: Heart failure; Renal dysfunction; Estimated glomerular filtration rate (eGFR) INTRODUCTION to monitor, treatment and prognosis of patients with HF Heart failure (HF) is a serious condition with high mortality despite all modern treatment Many factors contribute to the poor outcome in HF Renal dysfunction occurs in acute and chronic HF, is associated with reduced survival [4, 5] Prevalance of renal dysfunction is common, related to prognosis, treatment of HF Otherwise, HF can have similarly detrimental effects on renal function This intersection between cardiac and renal insufficiencies, the so-called “cardio-renal” interaction is associated with increased rates of morbidity and mortality in patients [8, 9] Therefore, investigation of renal dysfunction is necessary Objectives: To determinate the prevalence, characteristics of renal dysfunction in HF patients and investigate the relationship between renal function and the degree of HF, ejection fraction, serum BNP SUBJECTS AND METHODS Subjects 95 patients with HF at Department of Cardiology, 103 Military Hospital from November 2016 to April 2017 For each patient, baseline data was recorded on the form including demography, causes of HF, clinical status, echocardiographic findings, serum B-type natriuretic peptide (BNP) * Corresponding author: Nguyen Oanh Oanh (oanha2.103@gmail.com) Date received: 05/03/2018 Date accepted: 24/03/2018 180 Journal of military pharmaco-medicine no5-2018 * Renal function: The measurement of renal function was carried out by estimated Glomerular Filtration Rate (eGFR) using the Modification of Diet in Renal Disease (MDRD) equation: eGFR = 0.881 × 186 × (serum creatinine + 0.2 in mg/dL)-1.154 × (age in years)-0.203 × (0.742 if female) mL.min-1.1.73m-2 All patients were.characterized by their renal function: normal (eGFR ≥ 90 mL·min-1·1.73m-2), light renal dysfunction (eGFR < 90 and ≥ 60 mL·min-1·1.73 m-2), moderate to severe renal dysfunction (eGFR < 60 mL·min-1·1.73 m-2) [9] * Statistical analysis: Data was processed using statistical methods in medicine with software package SPSS version 21.0 for windows RESULTS Patient characteristics Table 1: Baseline patient characteristics according to baseline eGFR -1 Characteristics Demography Age (years) (mean ± SD) Male, (%) BMI, (kg/m ) Cause of HF, (%) Ischemic Hypertension Diabetes mellitus Hb concentration, (g/L) NYHA functional class NYHA II NYHA III NYHA IV Serum BNP, (pg/mL) Total (n = 95) -2 eGFR (mL.min ·1.73 m ) p < 60 (n = 50) ≥ 60 (n = 45) 70.2 ± 12.5 66.3 21.1 ± 2.6 73.4 ± 12.2 58.0 21.2 ± 4.0 66.1 ± 14.0 63.4 21.5 ± 4.5 < 0.05 > 0.05 > 0.05 24.4 51.6 19.0 36 64 22 11.1 37.7 15.5 < 0.05 < 0.05 > 0.05 124.1 117.0 ± 19.8 130.2 ± 20.6 < 0.05 3.21 ± 0.67 13 (13.6%) 49 (51.6%) 33 (34.8%) 3.34 ± 0.63 (6%) 32 (64%) 15 (30%) 3.06 ± 0.69 10 (24.2%) 17 (37.8%) 18 (40%) < 0.05 1511.8 ± 1445.7 1875.0 ± 1612.8 1108.2 ± 1117.4 < 0.01 Mean age, BNP and NYHA function class of the patients with eGFR < 60 ml.min.1.73 m-2 was higher than that of the patients with eGFR 60 ml.min-1.1.73 m-2 Figure 1: Distribution of eGFR The majority of HF patients had eGFR < 60 ml.min-1.1.73m-2 (64.41%) 181 Journal of military pharmaco-medicine no5-2018 Figure 2: Relationship between eGFR and LVEF The rate of patients with eGFR < 60 ml.min -1.1.73m -2 in the group LVEF < 50% was almost twice as high as that of the group LVEF ≥ 50% This difference is statistically significant (r = 0.521316; p < 0.001; eGFR = 0.9224 LVEF + 21.386) Figure 3: The correlation between eGFR and LVEF There was a significant positive correlation between eGFR and LVEF The linear regression showed that EF decreased by 1% when the eGFR decreased 0.9224 mL.min-1.1.73m-2 182 Journal of military pharmaco-medicine no5-2018 (r = -0.251108304; p < 0.01; eGFR = -0.0043[BNP] + 68.678) Figure 4: The correlation between eGFR and serum BNP level There was a significant reversal correlation between eGFR and serum BNP levels The linear regression showed that serum BNP levels increased by 100 pg.ml-1, whereas the eGFR decreased by 0.43 mL.min-1.1.73m-2 DISCUSSION General characteritics of HF patients with renal dysfunction Table shows mean age of this study group was 70.2 ± 12.5 years and 66.3% were males HF etiology was ischemic in 24.4%, hypertensive in 51.6%and diabetes mellitus in 19.0%, which was similar to that reported in previous cohort studies and clinical trials The level of GFR is usually regarded as the best overall index of the level of kidney function Serum creatinine is determined by a number of factors, other than GFR, such as gender, age, muscle mass and ethnicity and therefore, it provides only a rough estimate of level of kidney function To provide a more accurate measure of kidney function, we estimated GFR using a recently validated formula from the MDRD study, which has been shown to be a more accurate measure of kidney function than serum creatinine or creatinine clearance estimated using either the Cockcroft Gault equation [9] The prevalence of CKD in this study (52.6%) was similar to that reported in previous cohort studies and clinical trials The previous cohort studies found 47 64% of HF patients with an eGFR < 60 mL.min-1.1.73m-2 The heart and kidney functions are closely linked together by haemodynamics, neurohormones and the sympathetic nervous system [3] The kidney is sensitive to haemodynamic changes, such as an increased central venous pressure (renal afterload) and a reduced cardiac 183 Journal of military pharmaco-medicine no5-2018 output (renal preload) In patients with decompensated HF, increased central venous pressure and/or intra-abdominal pressure are strong determinants of increased serum creatinine levels Reduced cardiac output is another major determinant of renal impairment in HF The kidneys are richly innervated by efferent sympathetic nerve fibres and the renal sympathetic drive is markedly increased in HF [5], [6] Table The prevalence of HF patients with eGFR < 60 mL.min-1.1.73m-2 in studies In the early stages of chronic HF, GFR is well-maintained by compensatory increases in filtration fraction; in patients with more severe chronic HF, GFR becomes more dependent on afferent arteriolar flow and the stimulation of hemodynamic and hormonal pathways Furthermore, the fall in effective renal blood flow is relatively more pronounced and therefore disproportional to the reduction in cardiac output Traditionally, the contribution of the kidneys to chronic HF has been considered as an adaptive response mechanism evoking a series of compensatory neurohormonal changes, in particular, increased adrenergic drive and activation of the RAAS to maintain perfusion to vital organs and to expand the inadequate arterial blood volume With respect to the kidneys, however, activation of the RAAS is not only a response to preserve systemic circulatory volume; indeed, it is primarily a response to preserve GFR as renal blood flow decreases and renal perfusion pressure declines Therefore, it could be postulated that the association between renal function and prognosis is linked by neurohormonal activation [5, 7] Our study 184 Author Year The number of HF patients The prevalence of HF patients with eGFR < 60 mL.min1 1.73m-2 Lofman I et al [4] 2016 47.716 51% 358 53% 2.013 70% 95 52.6% Rusinaru D et al 2011 [8] Hamaguchi et al [3] S 2009 2017 In our registry, for reduced kidney function, the patients who were older and more often suffered from hypertension and ischemic heart disease as seen in other studies They also often had more severe NYHA class, in line with other previous studies Table shows the mean NYHA functional class was 3.34 ± 0.63 for eGFR < 60 mL.min -1.1.73m-2 higher than 3.06 ± 0.69 for eGFR ≥ 60 mL.min-1.1.73m-2 (p < 0.05) Hamaguchi S et al studied 2,013 patients: mean NYHA functional class was 3.3 ± 0.7 There was 3.2 ± 0.7 for eGFR ≥ 60 mL.min-1 1.73m -2 (n = 579), 3.3 ± 0.7 for 30 ≤ eGFR < 60 mL.min -1 1.73m -2 (n = 1,025) and 3.4 ± 0.6 for eGFR < 30 mL.min-1.1.73m-2 (n = 409) The difference was significant statistically (p < 0.001) [3] * Relationship between eGFR and LVEF: Figure demonstrates that there is a high prevalence of reduced kidney function in patients with left ventricular dysfunction Reduced kidney function is associated with a higher prevalence of Journal of military pharmaco-medicine no5-2018 risk factors for mortality, for example lower ejection fraction and higher NYHA functional class This is consistent with previous studies that suggest a higher prevalence of cardiac risk factors in patients with greater reduction in kidney function and above 80% in patients with severe kidney dysfunction [4] GFR is a significant predictor of mortality in advanced HF patients who received CRT A 6-month GFR improvement after CRT implant is significantly associated with a lower hazard of mortality [2] Decreased renal function has been consistently demonstrated as an independent risk for all-cause mortality, as well as cardiovascular adverse outcomes in patients with chronic HF [1, 5] Hamaguchi S et al studied a broad sample of patients hospitalized with worsening HF and their outcomes with an average of 2.4 years of follow-up The multivariable adjusted risk for all-cause death or rehospitalization increased with reduced eGFR; an adjusted hazard ratio (HR) 1.520 (95% confidence interval (CI) 1.186 - 1.949) for eGFR 30 - 59 mL.min-1.1.73m-2 (p = 0.001) and HR 2.566 (95%CI 1.885 - 3.492) for eGFR < 30 mL.min-1.1.73m-2 or patients with dialysis (p < 0.001) [3] Figure shows there was a significant linear correlation between eGFR and LVEF with r = 0.54 (p < 0.001) Because of left ventricular systolic dysfunction, the left ventricular reduced to pump blood into the aorta artery to organs including the kidneys Anemia to the kidneys reduces glomerular filtration As a result, the eGFR decreases when the ventricular ejection fraction decreases Bansal, N et al showed that the LVEF index for lower glomerular filtration rate was lower than for those without renal function Renal dysfunction was strongly associated with short-term and long-term outcomes in patients with HF Having studied 47,716 patients in the Swedish HF Registry, Lofman I et al found there was an increasing mortality with decreasing kidney function In hospitalized patients, the in-hospital mortality increased from 2% in those with normal kidney function (eGFR > 90) to 30% in those with end stage renal disease (ESRD) (eGFR < 15) For 5-year mortality, this cumulative probability of death was above 60% in those with moderate kidney dysfunction Villacorta H et al studied a total of 209 patients with chronic and stable HF, of whom 90 had HFrEF and 119 had HFnEF The glomerular filtration rate was smaller in HFrEF group (57.6 ± 66.2 versus 94.8 ± 36.6 mL.min-1.1.73m-2; p = 0.01) Moderate to severe renal dysfunction (RD) prevalence was twice higher in HFrEF group (32.2% versus 16.8%; p = 0.01) [9] HFrEF patients presented renal dysfunction more frequently than HFnEF patients It is important to emphasize that though it is more prevalent in HFrEF patients, almost 20% of HFnEF patients presented moderate or severe risk of renal function, which suggests that renal endangering in HF comprises other mechanisms besides 185 Journal of military pharmaco-medicine no5-2018 low cardiac debt and bad renal perfusion typical of HFrEF patients Actually, it is known that the increase in central venous pressure, which leads to an increase in renal veins pressure, is one of the mechanisms involved in cardiac-renal syndrome and could explain its genesis in HFnEF patients [9] * Relationship between eGFR and BNP: BNP is synthesized, stored and excreted by ventricular tissue in response to increased volume and pressure overload The main physiological role of BNP is to protect the cardiovascular system and other systems against the overload phenomenon For chronic HF patients with worsening renal function (eGFR < 60 mL.min-1.1.73m-2), the volume overload increases serum BNP levels On the other hand, BNP are cleared by the kidney Thus, impaired renal function reduces BNP clearance and increases serum BNP levels There was a strong association between renal dysfunction and level of BNP/NT-ProBNP Evaluation of both BNP/NT-ProBNP and GFR in patients with HF might prove valuable in the evaluation of both shortand long-term prognosis [10] In this study, for reduced kidney function, the patients had higher serum BNP level, consistent with other previous studies The serum BNP was 1,875.0 ± 1612.8 pg.mL-1 for eGFR < 60 mL.min-1.1.73m-2 higher than 1108.2 ± 1117.4 pg.ml-1 for eGFR ≥ 60 mL.min-1.1.73m-2 (p < 0.05) There was a linear reversal correlation between eGFR and serum BNP level with r = -0.25 (p < 0.01) The more 186 increasing the serum BNP level was, the more decreasing eGFR was Hamaguchi S et al found: the mean serum BNP was 902 1026 pg.mL-1 There was 598 586 pg.mL-1 for eGFR ≥ 60 mL.min1 1.73m -2 (n = 579), 880 783 pg.mL -1 for 30 ≤ eGFR < 60 mL.min -1 1.73m -2 (n = 1,025) and 1,422 1,704 pg.mL-1 for eGFR < 30 mL.min-1.1.73m-2 (n = 409) The difference was significant statistically (p < 0.001) [3] CONCLUSION Renal dysfunction is common in patients with HF The more severe HF was, the less eGFR was Estimated GFR correlated positively with LVEF and negatively with BNP concentration in patients with HF REFERENCES Damman K, Valente M.A, Voors A.A et al Renal impairment, worsening renal function and outcome in patients with HF: an updated meta-analysis European Heart Journal 2014, 35, pp.455-469 Gronda E, Genovese S, Padeletti L et al Renal function impairment predicts mortality in patients with chronic HF treated with resynchronization therapy Cardiology Journal 2015, 22, 459-466 Hamaguchi S, Tsuchihashi-Makaya M, Kinugawa S et al Chronic kidney disease as an independent risk for long-term adverse outcomes in patients hospitalized with HF in Japan Report from the Japanese Cardiac Registry of HF in Cardiology (JCARE-CARD) Circulation Journal: official Journal of Japanese Circulation Society 2009, 73, pp.1442-1447 Journal of military pharmaco-medicine no5-2018 Lofman I, Szummer K, Hagerman I et al Prevalence and prognostic impact of kidney disease on HF patients Open Heart 2016, 3, e000324 Lullo L.D, Bellasi A, Barbera V et al Pathophysiology of the cardio-renal syndromes types 1-5: An up-to-date Indian Heart Journal 2017, 69 (2017), pp.255-265 Metra M, Cotter G, Gheorghiade M et al The role of kidney in HF European Heart Journal 2012, 33, pp.2135-2142 Ronco C, Cicoira M, McCullough P.A et al Cardiorenal Syndrome Type 1: Pathophysiological Crosstalk Leading to Combined Heart and Kidney Dysfunction in the Setting of Acutely Decompensated HF' JACC 2012, September 18, Vol 60, No12, pp.1031-1042 Rusinaru D, Buiciuc O, Houpe D et al Renal function and long-term survival after hospital discharge in HF with preserved ejection fraction International Journal of Cardiology 2011, 147, pp.278-282 Villacorta H, Saenz-Tello B.F, Santos E.B et al Renal dysfunction and anemia in patients with HF with reduced versus normal ejection fraction Arquivos brasileiros de cardiologia 2010, 94, 357-363, 378-384 10 Waldum B, Stubnova V, Westheim AS, Omland T et al Prognostic utility of B-type natriuretic peptides in patients with HF and renal dysfunction Clinical Kidney Journal 2013, 6, pp.55-62 187 ... that the increase in central venous pressure, which leads to an increase in renal veins pressure, is one of the mechanisms involved in cardiac -renal syndrome and could explain its genesis in HFnEF... intra-abdominal pressure are strong determinants of increased serum creatinine levels Reduced cardiac output is another major determinant of renal impairment in HF The kidneys are richly innervated... creatinine + 0.2 in mg/dL)-1.154 × (age in years)-0.203 × (0.742 if female) mL.min-1.1.73m-2 All patients were.characterized by their renal function: normal (eGFR ≥ 90 mL·min-1·1.73m-2), light renal