Journal of Cardiac Failure Vol. 19 No. 12 2013

Clinical Trials

Worsening Renal Function in Patients With Acute Decompensated Heart Failure Treated With Ultrafiltration: Predictors and Outcomes EUGENIA RAICHLIN, MD,1 NICHOLAS A. HAGLUND, MD,1 IOANA DUMITRU, MD,1 ELIZABETH R. LYDEN,2 MICHAEL D. JOHNSTON, MD,1 JOAN M. MACK, APRN,1 JOHN R. WINDLE, MD,1 AND BRIAN D. LOWES, MD, PhD1 Omaha, Nebraska

ABSTRACT Background: Ultrafiltration (UF) is used to treat patients with diuretic-resistant acute decompensated heart failure. The aim of this study was to identify predictors and the effect of worsening renal failure (WRF) on mortality in patients treated with UF. Methods and Results: Based on changes in serum creatinine, 99 patients treated with UF were divided into WRF and control groups. Overall creatinine increased from 1.9 6 9.7 to 2.2 6 2.0 mg/dL (P ! .001), and WRF developed in 41% of the subjects. The peak UF rate was higher in the WRF group in univariate analysis (174 6 45 vs 144 6 42 mL/h; P 5 .03). Based on multivariate analysis, aldosterone antagonist treatment (odds ratio [OR] 3.38, 95% confidence interval [CI] 1.17e13.46, P 5 .04), heart rate #65 beats/ min (OR 6.03, 95% CI 1.48e48.42; P 5 .03), and E/E0 $15 (OR 3.78, 95% CI 1.26e17.55; P 5 .04) at hospital admission were associated with WRF. Patients with baseline glomerular filtration rate (GFR) #60 mg/dL who developed WRF during UF had a 75% 1-year mortality rate. Conclusions: WRF occurred frequently during UF. Increased LV filling pressures, lower heart rate, and treatment with aldosterone antagonist at hospital admission can identify patients at increased risk for WRF. Patients with baseline GFR #60 mg/dL and WRF during UF have an extremely high 1-year mortality rate. (J Cardiac Fail 2013;19:787e794) Key Words: Acute decompensated heart failure, worsening renal function, ultrafiltration.

End-stage heart failure is a progressive disease associated with high rates of morbidity, mortality, and frequent hospitalization rates.1 Loop diuretics remain the mainstay of decongestive therapies for patients with acute decompensated heart failure (ADHF), however, they cause neurohormonal and sympathetic activation, electrolyte

abnormalities, worsening renal function (WRF), and ultimately diuretic resistance.2 In advanced stages of heart failure (HF), diuretic therapy may provide inadequate relief of congestion and has been associated with longer hospital stays and increased mortality,3 underscoring the importance of alternative decongestive strategies to manage volume overload and improve outcomes in this patient population. Venovenous ultrafiltration (UF) is an effective method for sodium and volume removal in patients resistant to diuretics.4 UF can be performed safely without detrimental hemodynamic consequences,5 and it may have advantages over diuretic use, including greater control over rate and volume of fluid removal, greater net loss of sodium due to removal of isotonic fluid, fewer electrolyte abnormalities, less neurohormonal activation, and decreased rate of HF hospital readmissions.6,7 Although UF can address

From the 1Division of Cardiology, College of Public Health, University of Nebraska Medical Center, Omaha, Nebraska and 2Department of Biostatistics, College of Public Health, University of Nebraska Medical Center, Omaha, Nebraska. Manuscript received April 3, 2013; revised manuscript received October 14, 2013; revised manuscript accepted October 29, 2013. Reprint requests: Eugenia Raichlin, MD, University of Nebraska Medical Center, 982265 Nebraska Medical Center, Omaha, NE 68198-2265. Tel: 402-559-5552; Fax: 402-559-7323. E-mail: [email protected] See page 793 for disclosure information. 1071-9164/$ - see front matter Published by Elsevier Inc. http://dx.doi.org/10.1016/j.cardfail.2013.10.011

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788 Journal of Cardiac Failure Vol. 19 No. 12 December 2013 diuretic resistance, it does not prevent WRF in patients with ADHF.6 In ADHF patients treated with diuretics, WRF has been associated with prolonged hospitalizations, higher inhospital costs, increased in-hospital mortality, and greater likelihood of hospital readmissions. The predictors of WRF and its clinical significance in patients undergoing UF remains unknown. The present study presents a single-center experience and assesses prevalence and clinical and echocardiographic predictors and outcomes of WRF in patients with advanced HF and diuretic resistance undergoing UF as rescue therapy. Methods The study protocol was approved by the University of Nebraska Medical Center Institutional Review Board. A total of 99 consecutive patients hospitalized for ADHF at the University of Nebraska Medical Center from January 2008 to December 2011 developed diuretic resistance and underwent UF for rescue therapy. Diuretic resistance was defined as progressive oliguria, worsening renal function, and persistent congestion despite intravenous diuretics use in dosages of O160 mg/day furosemide equivalent. Exclusion criteria were serum creatinine O3.5 mg/dL, inability to obtain venous access, and contraindications to anticoagulation. Patients were divided into WRF and non-WRF groups based on changes in serum creatinine during UF. WRF was defined as a rise in the serum creatinine level of O0.3 mg/dL.8,9 Additionally, renal function was assessed by calculating the glomerular filtration rate (GFR) with the use of the abbreviated Modification of Diet in Renal Disease equation: GFR 5 186  (serum creatinine [mg/dL])1.154  (age [y])0.203  0.742 (if female).10 The equation has previously been validated in the general and HF populations.11 Ultrafiltration Protocol All diuretics were discontinued at the time of initiation and for the duration of the UF intervention. Chronic maintenance medications, such as beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, aldosterone antagonists, and digoxin, were continued throughout the hospitalization, as tolerated, in all patients. Vasoactive drugs were used in patients with hemodynamic instability. Fluid status was managed by means of UF with the use of the Aquadex Flexflow device (Gambro UF Solutions, Brooklyn Park, Minnesota) as previously described.12 Vascular access was obtained with a peripherally inserted catheter placed at the bedside by trained registered nurses. Adjustments to the UF rate and duration of therapy were driven by clinical and hemodynamic goals (symptoms of congestion, volume burden, and systemic blood pressure [BP]) by the cardiologist in collaboration with nephrologists. A standard anticoagulation protocol using intravenous heparin to maintain the partial thromboplastin time in the range of 65e85 seconds was used on all of the patients undergoing UF. All of the patients were placed on a low-sodium diet (#2,000 mg/d) and a 2,000 mL fluid restriction per standard ADHF hospital protocol and were managed by registered nurses knowledgeable in advanced HF and specifically trained in UF. Patient demographic and clinical data were obtained from retrospective review of the medical records. Death was retrospectively recorded up to June 1, 2012.

All echocardiograms were performed at UNMC with a standardized protocol using current American Society of Echocardiography recommendations13 and clinical echocardiographic interpretations. Statistics Data are presented as mean 6 standard deviation for numeric values and percentage and count for categoric variables. The distribution of continuous variables was tested to ensure that normality assumptions were fulfilled. Variables with a heavily skewed distribution are reported as median with first and third quartiles (IQR). Clinical, hemodynamic, and echocardiographic data in the WRF group versus the non-WRF group were compared with the 2-tailed t test for numeric data and the chi-square test for categoric data. Subsequently the analysis of covariance accounting for baseline measurement was used to test for differences between clinical, hemodynamic, and echocardiographic characteristics before and after UF treatment. Collinearity diagnostics were performed to look for multicollinearity between the echocardiographic variables in the linear models. Weak collinearity between pulmonary arterial systolic pressure (PASP) and E/E0 was present (t 5 0.3; P 5 .01), and the latter was included in the final multivariate models. Stepwise backward logistic regression analysis was used to identify predictors of WRF and to estimate the relative contributions of the baseline clinical and echocardiographic variables to worsening kidney function during UF. Variables with P # .5 were factored into the model. Correlation coefficients of creatinine and blood urea nitrogen (BUN) changes during diuretic treatment and UF were calculated according to Spearman. Survival data was described with the use of the Kaplan-Meier method, and the log-rank test was used to compare groups. A P value of #.05 was considered to be statistically significant.

Results Patient baseline characteristics are presented in Table 1. In the whole study population, WRF developed in 40 patients (41%). There was no significant difference in baseline demographic characteristics between the non-WRF and WRF groups. A greater number of patients in the WRF group were treated with an aldosterone antagonist at a median dose of 25 (IQR 12.5e50) mg or with a combination of aldosterone antagonist and ACE inhibitor. There was a trend for greater use of ACE inhibitors in the WRF group. The furosemide-equivalent diuretic dose before initiation of UF was 217 6 711 mg and did not differ between the groups. Overall, 40% of patients had GFR #60 mg/dL, (41% of non-WRF and 40% of WRF; P 5 .89) before the UF treatment. The median duration of the hospitalization was 9 (IQR 6e15) days. There was no difference between the groups in the duration of UF, the amount of removed fluid or amount of weight lost (Table 2). Peak UF rate, however, was significantly higher in the WRF group compared with the non-WRF group. Nineteen WRF patients (48%) and 14 non-WRF patients (23%) underwent UF with peak rate O150 mL/h (P 5 .01). Peak UF rate O150 mL/h

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Table 1. Baseline Demographic and Clinical Data

Age, y Men, n (%) White, n (%) Ischemic cardiomyopathy, n (%) Inotropes Milrinone, n (%) Dobutamine, n (%) Dopamine, n (%) Beta-blocker, n (%) ACEI, n (%) AA, n (%) Combined ACEI and AA, n (%) Isosorbide, n (%) Hydralazine, n (%) Allopurinol, n (%) Statin, n (%) Diabetes mellitus, n (%) IV Furosemide dose (mg)

Overall (n 5 99)

Non-WRF (n 5 59; 59%)

WRF (n 5 40; 41%)

P Value

64 6 44 61 (62) 83 (85) 41 (45)

65 6 55 40 (68) 48 (83) 26 (47)

64 6 42 21 (53) 35 (88) 15 (41)

.59 .13 .59 .57 .93

29 (29) 17 (17) 2 (2) 75 (77) 59 (60) 16 (17) 13 (14) 51 (52) 14 (21) 13 (14) 36 (37) 60 (62) 217 6 111

18 (31) 11 (19) 1 (2) 43 (73) 33 (56) 4 (6) 3 (6) 29 (49) 6 (15) 8 (17) 22 (37) 34 (59) 221 6 114

11 (28) 6 (15) 1 (3) 32 (80) 26 (65) 12 (32) 10 (24) 22 (55) 8 (30) 5 (15) 14 (36) 27 (68) 212 6 109

.72 .09 .007 .03 .10 .33 .79 .83 .37 .89

ACEI, angiotensin-converting enzyme inhibitor; AA, aldosterone antagonist.

was associated with odds ratio (OR) of 1.23 for WRF by the end of UF (95% confidence interval [CI] 1.23e5.89). Urine output during UF treatment did not differ between the groups (3.10 6 0.3 L in the non-WRF group and 2.4 6 4.3 L in the WRF group; P 5 .16). Kidney function did not differ between the groups at hospital admission: BUN was 43.00 6 01.54 and 42.23 6 39.16 (P 5 .9) and creatinine was 1.71 6 1.61 and 1.78 6 8.55 (P 5 .52) in non-WRF and WRF groups, respectively. The values of BUN and creatinine at start UF are presented in Table 1. During diuretic treatment before initiation UF, there was increase in creatinine (P 5 .015) and nonsignificant change in BUN (P 5 .21) in the non-WRF group. In the WRF group, BUN (P 5 .05) and creatinine (0.03) increased significantly. Changes in BUN and creatinine while on diuretic treatment did not differ between the groups. There was no correlation between changes in creatinine (r 5 0.2; P 5 .08) and BUN (r 5 0.1; P 5 .4) during diuretic treatment and UF. Overall, BUN increased by 10.66 6 69.28 mg/dL (P ! .001), creatinine increased by 0.34 6 4.78 mg/dL (P ! .001), and GFR decreased by 7.32 6 21.65 mg/dL (P 5 .012) compared with baseline. Uric acid level decreased by 0.8 6 8.11 mg/dL (P 5 .0014) in all patients. The difference was significant in the non-WRF group (Table 2). Overall, sodium decreased by 3.13 6 3.23 mg/dL, and the changes were significant in both groups. Thirty-one patients (32%) presented with hyponatremia (Na !135 mg/ dL) before UF and 61 patients (62%) developed hyponatremia by the end of UF (Table 2). There was no difference between the groups in liver function tests before or after UF treatment. Hemodynamic and baseline echocardiographic characteristics are presented in Table 3. Systolic and diastolic BP at baseline was similar between the groups. Blood pressure decreased during UF, and the changes in BP did not differ between the groups. There was no significant

difference between the groups in episodes of hypotension: 55% versus 61% of patients in the non-WRF and the WRF groups, respectively, had $1 episode of decrease in systolic BP to #80 mm Hg (P 5 .51). ACE inhibitors were discontinued in 9 non-WHL patients (15%) and 12 WHN patients (30%; P 5 .08), and beta-blockers were discontinued in 14 non-WHL patients (24%) and 18 WHN patients (45%; P 5 .03). Heart rate at the start of UF was lower in the WRF group and did not change significantly during the UF period. Four non-WRF patients (7%) and 12 WRF patients (30%) had a heart rate #65 beats/min at the start of UF (P 5 .002). Heart rate #65 beats/min was associated with an OR 5.79 (95% CI 1.71e19.52) for WRF by the end of UF. There was no difference in systolic and diastolic BP at baseline or number of hypotension episodes during UF treatment in patients with baseline HR !65 or $65 beats/min. Patient echocardiographic characteristics are presented in Table 1. Echocardiography at admission showed higher relative wall thickness in the WRF group (0.49 6 9.12 vs 0.44 6 4.11; P 5 .03) and no significant difference between the groups in left ventricular mass (LVM; 292.72 6 27.87 g vs 264.51 6 19.71 g; P 5 .10). The prevalence of concentric hypertrophy (CH) pattern was higher and the prevalence of eccentric hypertrophy (EH) pattern lower in the WRF group than in the non-WRF group (Table 3). LVM/left ventricular (LV) end-diastolic volume was also higher in the WRF group (2.86 6 6.89 vs 2.23 6 3.92, P 5 .04). Seven patients (12%) versus 9 (23%) had left ventricular ejection fraction (LVEF) O45% in the non-WRF and the WRF groups respectively (P 5 .16; Table 3). WRF patients had higher E/E0 and a larger number of WRF-patients had E/E0 $15. E/E0 $15 was associated with an OR 2.78 (95% CI 1.08e7.14) for WRF by the end of UF. There was no difference in LAVI between the groups. Right ventricular (RV) diastolic dimension and

790 Journal of Cardiac Failure Vol. 19 No. 12 December 2013 Table 2. Changes in Laboratory and Hemodynamic Data During Ultrafiltration (UF) Treatment

Peak UF rate, mL/h Peak UF rate O150 mL/h, n (%) Duration of UF (d) Fluid removed (L) Urine output during UF (L) BUN at start UF (mg/dL) BUN at end UF (mg/dL) P value* Creatinine at start of UF (mg/dL) Creatinine at end of UF (mg/dL) P value* GFR at start of UF (mg/dL) GFR at end of UF (mg/dL) P value* Weight at start of UF (kg) Weight at end of UF (kg) P value* Uric acid at start of UF (mg/dL) Uric acid at end of UF (mg/dL) P value* Hemoglobin at start of UF (mg/dL) Hemoglobin at end of UF (mg/dL) P value* Albumin at start of UF (mg/dL) Albumin at end of UF (mg/dL) P value* Na at start of UF (mg/dL) Na at end of UF (mg/dL) P value* Na # 135 at start of UF, n (%) Na # 135 at end of UF, n (%) P value* Bilirubin at start of UF (mg/dL) Bilirubin at end of UF (mg/dL) P value* Sinus rhythm, n (%) Atrial fibrillation, n (%) Paced rhythm, n (%)

Non-WRF (n 5 59; 59%)

WRF (n 5 40; 41%)

P Value

143.90 6 52.39 14 (23) 3.0 (2.0; 4.7) 9.85 6 6.94 3.10 6 0.3 46.03 6 21.09 48.64 6 22.46 .94 1.86 6 0.68 1.77 6 0.62 .02 66.52 6 42.60 65.18 6 48.44 .25 102.64 6 25.41 95.088 6 24.27 !.0001 9.10 6 2.63 7.97 6 2.17 .0002 10.95 6 1.70 10.66 6 1.44 .70 3.31 6 0.60 3.09 6 0.58 .13 137.20 6 4.00 133.84 6 4.72 !.001 15 (25) 34 (58) .04 1.05 6 0.65 1.02 6 0.67 .77 28 (49%) 25 (45) 16 (27)

174.25 6 74.90 19 (48) 2.6 (1.7; 4.9) 9.69 6 7.68 2.4 6 4.3 46.70 6 20.56 69.44 6 29.84 !.0001 1.93 6 0.68 2.93 6 1.10 .0001 69.01 6 42.42 43.62 6 33.23 .0001 103.81 6 30.65 96.71 6 28.05 !.0001 10.16 6 2.68 9.84 6 4.27 .42 11.14 6 1.62 11.22 6 2.45 .74 3.24 6 0.54 3.17 6 0.43 .35 135.98 6 4.02 133.13 6 6.58 .003 16 (40) 27 (67) .41 1.09 6 0.57 1.00 6 0.63 .55 20 (46%) 13 (31) 13 (33)

.03 .01 .47 .92 .16 .93 !.001y .66 !.001y .88 !.001y .84 .96y .12 .014y .69 .84y .67 .21 .15 .97y .20 .73y .74 .49y .96 .18 .57

BUN, blood urea nitrogen; GFR, glomerular filtration rate. *Paired t test. y Analysis of covariance with the use of baseline characteristic as covariance.

RV/LV diastolic dimensions were higher in the WRF group than in the non-WRF group. PASP also was higher in the WRF group. There was no significant difference in LV systolic and diastolic volumes or LVEF. Incidence of moderate or severe tricuspid and mitral regurgitation did not differ between the groups. Multivariate analysis was performed with the use of the following univariate predictors of WRF: aldosterone antagonist treatment, peak UF rate O150 mL/h, heart rate #65 beats/min, baseline LV geometry, E/E0 $15, RV diastolic dimension, RV/LV diastolic dimensions, and PASP. Based on multivariate analysis, aldosterone antagonist treatment, heart rate #65 beats/min, and E/E0 $15 were independently associated with WRF during UF (Table 4). Clinical Outcome

The median duration of follow-up was 12.2 (IQR 6.8e20.6) months from hospital admission. The WRF was associated with increased length of the index hospitalization (13.9 6 94.1 d vs 8.9 6 9.8 d; P 5 .03). Patients

were stratified into 4 subgroups based on baseline GFR at admission and changes in GFR during UF: 1) non-WRF, baseline GFR O60 mg/dL (n 5 34); 2) WRF, baseline GFR O60 mg/dL (n 5 24); 3) non-WRF, baseline GFR #60 mg/dL (n 5 24); and 4) WRF, baseline GFR #60 mg/dL (n 5 17). Survival rates in these subgroups were 94%, 80%, 80%, and 54%, respectively, at 6 months and 61%, 75%, 48%, and 25% at 12 months (P 5 .025; logrank test; Fig. 1). Discussion The key findings of our study were: 1) Initiation of UF as a rescue therapy for decongestion in patients admitted with refractory end-stage HF and diuretic resistance often further compromises renal function and worsens hyponatremia; 2) treatment with aldosterone antagonist, preexisting heart rate #65 beats/min, and increased LV filling pressure (E/E0 $15) by echocardiogram at the time of hospital admission can identify patients at increased risk for WRF during UF

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Table 3. Hemodynamic and Echocardiographic Characteristics

Systolic BP at start of UF (mm Hg) Sustolic BP at end of UF (mm Hg) P value* Diastolic BP at start of UF (mm Hg) Diastolic BP at end of UF (mm Hg) P value* Heart rate at start of UF (beats/min) Heart rate at end of UF (beats/min) P value* Herat rate #65 beats/min at start of UF, n (%) Heart rate #65 beats/min at end of UF, n (%) P value* LV geometry: NG/CR/CH/EH, n (%) LVEF (%) LVEF $45%, n (%) Moderate /severe mitral regurgitation, n (%) E/E0 , n (%) E/E0 $15 Left atrial volume index RV diastolic dimension (mL) RV/LV diastolic dimension Moderate-severe RV dysfunction, n (%) Moderate-severe tricuspid regurgitation, n (%) PASP (mm Hg)

Non-WRF (n 5 59; 59%)

WRF (n 5 40; 41%)

P Value

117 6 23 104 6 23 .0007 63 6 12 57 6 10 .035 79 6 13 81 6 13 .28 4 (7) 5 (8) .31 6 (10)/7 (12)/19 (32)/27 (46) 35 6 19 7 (12) 18 (30) 15.52 6 6.62 18 (31) 47.72 6 14.11 41.26 6 7.30 0.76 6 0.16 22 (37) 33 (55) 57.87 6 16.17

113 6 19 104 6 45 .015 62 6 11 60 6 11 .13 72 6 18 76 6 14 .14 12 (30) 13 (32) .25 0/4 (10)/23 (58)/13 (32) 37 6 19 9 (23) 12 (30) 19.57 6 7.71 22 (55) 48.15 6 15.22 44.06 6 5.21 0.87 6 0.25 17 (43) 21 (52) 65.05 6 18.58

.44 .96y .78 .84y .05 .42y .002 .003 .016 .74 .16 .79 .02 .03 .89 .04 .03 .45 .60 .05

BP, blood pressure; UF, ultrafiltration; LV, left ventricular; NG, normal geometry; CR, concentric remodeling; CH, concentric hypertrophy; EH, eccentric hypertrophy; LVEF, left ventricular ejection fraction; RV, right ventricular. *Paired t test. y Analysis of covariance with the use of baseline characteristic as covariance.

therapy; and 3) patients with ADHF and baseline GFR #60 mg/dL who developed WRF during UF have a 75% mortality rate at 1 year from index hospitalization. Worsening Renal Function

Chronic kidney disease is present in 30%e40% of patients with HF, with an even greater prevalence in those with more severe symptoms.14 Decongestive treatment with diuretics in patients with chronic HF may lead to diuretic resistance and progression of kidney injury and WRF, otherwise known as cardiorenal syndrome type 2.15 Although UF is an effective method to relieve congestion by sodium and volume removal, earlier studies failed to show beneficial renal effects with UF compared with diuretic therapy.16e18 The present study is consistent with those earlier findings, though showing an even greater incidence of WRF (41% of patients).6,18,19 In contrast to randomized UF studies, our findings reflect realworld experience with UF. In this study, patients received UF to relieve congestive symptoms because of diuretic refractoriness when all other therapeutic decongestive options had failed. Moreover, our study population had more advanced Table 4. Predictors of Worsening Renal Failure After ultrafiltration (UF), Multivariate Nominal Logistic Regression Analysis

Aldosterone antagonist treatment E/E0 $15 before UF Heart rate #65 beats/min before UF

OR

95% CI

P Value

3.38 3.78 6.05

1.17e13.46 1.26e17.55 1.48e48.42

.042 .037 .033

OR, odds ratio; CI, confidence interval.

HF requiring vasoactive therapies in 48% of patients, significantly more often than in recent randomized UF studies.6,18 Finally, in contrast to immediate UF after hospital admission in the UNLOAD and CARRESS-HF studies,6,18 in our study UF was initiated after failed attempts to relieve congestion by medical therapy and frequently after the onset of WRF caused by diuretics. Although up-front use of UF did not translate into clinical benefit in an ADHF patient population,20 the role of the preexisting diuretic-induced renal damage is still unclear. Indeed, our study did not find a correlation between changes in kidney function during diuretic treatment and UF. Hyponatremia is common in patients with HF and its progression during hospitalization is a robust predictor of poor cardiac prognosis in ADHF patients.21 UF has been considered to correct hyponatremia in symptomatic patients refractory to diuretics in European HF guidelines.22 This recommendation, however, is not supported by our findings and other reports.16,18 Our data showed a significant decrease in plasma sodium levels during UF. Moreover, the number of patients with hyponatremia almost doubled during UF treatment. The underlying pathophysiology of hyponatremia in the setting of UF is unclear. Fluid removed by UF is isotonic to plasma whereas urine in patients treated with IV diuretics is hypotonic,23 suggesting that hyponatremia occurs secondary to increased sodium excretion during UF. UF may cause elevation of arginine-vasopressin production, which leads to hyponatremia via stimulation of the V2 receptors. The role of vasopressin receptor antagonists in patients treated with UF is unknown.

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Fig. 1. Estimated survival during 12 months’ follow-up after ultrafiltration. WRF, worsening renal failure; GFR, glomerular filtration rate.

Patients with HF are prone to develop hyperuricemia, which is associated with increased morbidity and mortality in patients with chronic HF.24 The present study demonstrated a decrease in uric acid during the UF treatment. These findings should be further evaluated. Hemodynamic impairment with low cardiac output and increased central venous pressure may cause a reduction in the GFR and resistance to diuretics.25 Historically, mechanisms invoked to explain WRF has been attributed to reduced cardiac index and overaggressive reduction in filling pressures whereby a decrease in blood flow to the kidneys leads directly to renal impairment. This theory, and specifically the importance of effective intravascular volume depletion as a causative mechanism for WRF, has not been confirmed in recent publications.25,26 Instead, venous congestion has been associated with cardiorenal comspromise in patients with ADHF.25 Marenzi et al demonstrated that UF was associated with intravascular volume stability and adequate plasma refill rates in patients with HF even at high rates of volume removal.5 However, the recently demonstrated potential adverse impact of UF on renal function in the setting of high UF rates and short duration of volume removal in the UNLOAD and CARRESS-HF trials brought into question whether exceeded plasma refill rates could have contributed to WRF.6,18 Indeed, in the present study, UF rates O150 mL/h increased the risk of WRF by univariate analysis, although urine output during UF did not differ statistically between the groups, and stable hematocrit and albumin values in both patient groups suggested that a proportional volume of fluid was refilled from the congested interstitium. This association, however, disappeared after multivariate analysis, indicating that renal dysfunction can not be fully explained by rate of fluid removal and likely depends on more complex interactions between central hemodynamics and different endogenous vascular factors. Cardiovascular reaction to transient hypovolemic is mediated through enhancement of heart rate via stimulation

of the sympathetic nervous system and activation of the renin-angiotensin-aldosterone system. Baseline heart rate !65 beats/min was the strongest risk factor for WRF during UF in our study. Fibrotic atrial remodeling, downstream deficits in b-adrenergic stimulation, autonomic dysfunction with reduced baroreflex sensitivity, and medications (betablockers, digoxin, amiodarone) may contribute to chronotropic incompetence. Inability to maintain adequate cardiac output in the setting of the intravascular volume depletion during UF may result in WRF during UF. We did not find, however, a difference in BP in patients with HR ! 65 or $65 beats/min, suggesting more complex pathophysiology of kidney dysfunction during UF. Effect of rateadaptive cardiac pacing strategies on renal outcomes was not evaluated in this study. Our data demonstrated that chronic treatment with aldosterone antagonists was associated with WRF during UF. Hypotension, shock, and kidney damage secondary to exhausted or medically blocked neurohormonal mechanisms may be a mechanism. Indeed, ACE inhibitors and betablockers have been discontinued more often in the WRF patients. Our study did not find a difference in BP or number of hypotension episodes between the groups; however, the duration of hypotension and titration of the dose of inotropes were not accounted for. The selection bias when sicker patients have been treated with aldosterone inhibitor and have developed WRF during UF can not be excluded. Moreover, aldosterone inhibitor was used in a small cohort of 17 patients overall, so its effect on WRF remains questionable. Interestingly, it was suggested in a rat study that spironolactone can prevent acute ischemic kidney injury.27 The prognostic significance of WRF in patients with end-stage HF receiving spironolactone has been evaluated in several randomized studies. Both the EPHESUS28 and the RALES29 studies demonstrated the lack of worsening of renal function after an initial relatively early decline in GFR, suggesting that WRF, secondary to reninangiotensin-aldosterone inhibition, does not necessarily reflect kidney injury but might result from alterations in renal hemodynamic status.30 Spironolactone treatmente induced WRF is not associated with an increased risk for mortality. Further investigation is needed to determine if dose modification or temporarily withholding neurohormonal blocking medications is necessary to prevent WRF in the setting of UF. Echocardiographically assessed LV systolic function did not differ between the groups. However, LV concentric hypertrophy and higher LV mass-volume ratio was associated with WRF after UF treatment in our study. Moreover, 12% of the non-WRF patients and 23% of the WRF patients had LVEF O45%. Although this difference did not achieve statistical significance, this data should be validated in a larger study. Increased LV filling pressure, as assessed by E/E0 , increased RV dimension, and elevated PASP, were univariate predictors of WRF after UF. Indeed, increased LV

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filling pressures may strongly influence RV function and cause RV dilatation primarily through increased RV afterload. RV dilation in response to chronic volume and pressure overload can be the first sign of RV dysfunction, which is associated with poor prognosis in HF patients.31 The majority of the patients with diuretic-refractory congestion had echocardiographic evidence of increased filling pressures at start UF; however, the E/E0 and the incidence of E/E0 O15 were significantly higher in the WRF cohort. Multivariate analysis showed that increased E/E0 was the strongest echocardiographic predictor of WRF in our study. Notably, our findings were consistent with the Mullens et al study, which found that patients with the highest filling pressures on discharge, despite the highest cardiac indices, had the greatest incidence of WRF.25 Mortality



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utilizing UF as a rescue decongestive and volume removal strategy after failure of standard medical decongestive therapies. Treatment with Aldosterone antagonists, preexisting low heart rate, and increased LV filling pressure as assessed by echocardiogram at hospital admission can identify patients at increased risk for WRF. Mortality was highest, 75% at 1 year, for patients who presented with GFR !60 mg/dL and developed WRF with UF therapy. This small, retrospective, hypothesis-generating study requires validation in larger prospective cohorts to delineate the role of UF as a rescue therapy in patients without other therapeutic decongestive options after diuretics have failed, to clarify the incidence and risk factors for WRF and to refine patient selection for UF. Disclosures None.

Although there were relatively low 60- and 90-day mortality rates in the CARRESS-HF (17%) and UNLOAD (9.6%) trials, the need to proceed with UF as a treatment of desperation, after exhausting attempts to relieve congestion with diuretics and vasoactive agents, clearly represented a patient population refractory to the medical therapy, and similarly to a earlier single-center series4,32 the overall 12-month mortality rate in our study was high, at 48%. Impaired kidney function at initiation of UF predicted the worse prognosis and WRF during UF in patients with GFR #60 mg/dL resulted in the highest mortality rate (46% at 6 months and 75% at 1 year). These patients may represent a cohort with more severe congestion, worse hemodynamic condition, and more severe intrinsic kidney disease. On the other hand, in patients with preserved renal function at the initiation of UF (GFR O60 mg/dL), WRF could be transient and not associated with worse clinical outcomes. Similarly, in the setting of diuretic treatment, several recent studies did not find an independent association between an acute increase in serum creatinine and survival.19,26 This suggests that prognosis is mostly related to chronic changes in kidney function and persistent congestion, rather than to transient WRF. Study Limitations

The present study has several limitations. First, it was retrospective in nature and can not establish causal relationships. The study does, however, represent a contemporary real-world advanced HF population with advanced cardiorenal syndrome and diuretic resistance who used UF as a rescue therapy and is therefore beneficial because it is generalizable. Conclusion This study demonstrated that WRF is common and occurs often in a real world ADHF patient population

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