JACC: Heart Failure 2013 by the American College of Cardiology Foundation Published by Elsevier Inc.
Vol. 1, No. 5, 2013 ISSN 2213-1779/$36.00 http://dx.doi.org/10.1016/j.jchf.2013.05.007
Tubular Damage and Worsening Renal Function in Chronic Heart Failure Kevin Damman, MD, PHD,* Serge Masson, PHD,y Hans L. Hillege, MD, PHD,*z Adriaan A. Voors, MD, PHD,* Dirk J. van Veldhuisen, MD, PHD,* Patrick Rossignol, MD, PHD,x Gianni Proietti, MD,k Savino Barbuzzi, MD,{ Gian Luigi Nicolosi, MD,# Luigi Tavazzi, MD,** Aldo P. Maggioni, MD,yy Roberto Latini, MDy Groningen, the Netherlands; Milan, Terni, Venosa, Pordenone, Cotignola, and Florence, Italy; and Nancy, France Objectives
This study sought to investigate the relationship between tubular damage and worsening renal function (WRF) in chronic heart failure (HF)
Background
WRF is associated with poor outcome in chronic HF. It is unclear whether urinary tubular markers may identify patients at risk for WRF.
Methods
In 2,011 patients with chronic HF, we evaluated the ability of urinary tubular markers (N-acetyl-beta-Dglucosaminidase (NAG), kidney injury molecule (KIM)-1, and neutrophil gelatinase-associated lipocalin (NGAL) to predict WRF. Finally, we assessed the prognostic importance of WRF.
Results
A total of 290 patients (14.4%) experienced WRF during follow-up, and WRF was a strong and independent predictor of all-cause mortality and HF hospitalizations (hazard ratio [HR]: 2.87; 95% CI: 2.40 to 3.43; p < 0.001). Patients with WRF had lower baseline glomerular filtration rate and higher KIM-1, NAG, and NGAL levels. In a multivariableadjusted model, KIM-1 was the strongest independent predictor of WRF (HR: 1.23; 95% CI: 1.09 to 1.39 per log increase; p ¼ 0.001).
Conclusions
WRF was associated with strongly impaired outcome in patients with chronic HF. Increased level of urinary KIM-1 was the strongest independent predictor of WRF and could therefore be used to identify patients at risk for WRF and poor clinical outcome. (GISSI-HF–Effects of n-3 PUFA and Rosuvastatin on Mortality-Morbidity of Patients With Symptomatic CHF; NCT00336336) (J Am Coll Cardiol HF 2013;1:417–24) ª 2013 by the American College of Cardiology Foundation
Renal dysfunction, one of the most common and most important comorbidities in chronic heart failure (HF) is associated with unfavorable outcome, including mortality. Additionally, the development of worsening renal function (WRF) further impairs clinical outcome, including mortality and HF hospitalizations (1,2). Therefore, identifying patients at risk for WRF might lead to better use of life-saving therapies, less frequent hospital visits, and maybe even improved outcome.
Recently, more interest has been shown in markers of tubular injury than serum creatinine because these markers are more sensitive and specific to early changes in renal function, whereas serum creatinine is slowly affected and is dependent on muscle mass and age. We recently showed
From the *Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; yDepartment of Cardiovascular Research, IRCCS - Istituto di Ricerche Farmacologiche “Mario Negri”, Milan, Italy; zDepartment of Epidemiology, University Medical Center Groningen, Groningen, the Netherlands; xINSERM, Centre d’Investigations Cliniques, and Université de Lorraine, INSERM U961, Nancy, France; kUO Cardiologia Territoriale, Ospedale di Terni, Terni, Italy; {Servizio di Cardiologia, Ospedale di Venosa, Venosa, Italy; #Azienda Ospedaliera Santa Maria degli Angeli, UO Cardiologia, Pordenone, Italy; and the **GVM Care and Research, Ettore Sansavini Health Science Foundation–Maria Cecilia Hospital, Cotignola, Italy; and the yyANMCO Research Center, Florence, Italy. The GISSI-HF trial is endorsed by the Associazione Nazionale Medici Cardiologi Ospedalieri, Florence, Italy, Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy,
and Consorzio Mario Negri Sud, Santa Maria Imbaro, Italy. SPA, Pfizer, Sigma Tau, and AstraZeneca contributed to fund the main study. AstraZeneca provided separate support for the microalbuminuria substudy. Drs. Masson, Maggioni, and Latini received institutional grants from AstraZeneca, SPA, Sigma Tau, and Pfizer. Dr. Maggioni received honoraria for lectures from AstraZeneca. Dr. Tavazzi served on the speakers bureaus for the companies that financed the GISSI-HF trial. Dr. van Veldhuisen received board membership fees from Vifor, Amgen, BG Medicine, Johnson & Johnson, and Sorbent. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Manuscript received March 4, 2013; revised manuscript received April 29, 2013, accepted May 3, 2013.
See page 425
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Damman et al. Tubular Damage and Worsening Renal Function
that these tubular damage markers confer excess risk in patients with chronic HF (3). eGFR = estimated However, the hypothetical glomerular filtration rate potential of these markers to HF = heart failure predict occurrence of deterioraKIM = kidney injury molecule tion of renal function over time NAG = N-acetyl-beta-Dhas not been evaluated in glucosaminidase patients with chronic HF. NGAL = neutrophil In the present substudy of the gelatinase-associated GISSI-HF (Gruppo Italiano per lipocalin lo Studio della Sopravvivenza WRF = worsening renal Nell’Infarto Miocardico) trial, we function set out to determine the prevalence of WRF, predictors of the occurrence of WRF and clinical significance of tubular markers in predicting WRF. Abbreviations and Acronyms
Methods The design and main results of the GISSI-HF trial have been described in detail elsewhere (4,5). The institutional review committee at each participating center approved the study, and all patients gave informed consent. A total of 2,130 patients provided a first-morning spot urine at any of the clinical visits scheduled in the trial. The mean time to urine sampling from randomization date in the trial was 1.2 years (range 0 to 3.5 years). Urine samples were stored at 70 C before analysis. Assessment of renal function, WRF, and tubular markers. Serum creatinine was measured, per protocol, at all clinical visits in local laboratories. Glomerular filtration rate (eGFR) (ml/min/1.73 m2) was estimated using the simplified modification of diet in renal disease formula. Baseline GFR was set at the time of urine collection. WRF was defined as 0.3 mg/dl and 25% increase in serum creatinine at any moment during follow-up. For sensitivity analysis, a reduction in eGFR >20% and an absolute increase >0.3 mg/dl in creatinine (both separately) were also considered. N-acetyl-beta-D-glucosaminidase (NAG), kidney injury molecule (KIM)-1, and neutrophil gelatinase-associated lipocalin (NGAL) levels were determined in urine (3). In short, NGAL was determined by means of a commercially available enzyme-linked immunosorbent assay (ELISA) kit from Antibody Shop (Gentofte, Denmark). NGAL was expressed in ng/ml (limit of detection 0.093 ng/ml). The enzymatic activity of NAG was evaluated using the substrate p-nitrophenyl N-acetyl-beta-D-glucosaminide (Sigma, St. Louis, Missouri; limit of detection 0.113 U/ml). Urinary KIM-1 measurements were performed using an ELISA (R&D Systems, Minneapolis, Minnesota; limit of detection 0.125 ng/ml). All urinary tubular marker concentrations were normalized to urinary creatinine concentrations to allow for correction for dilution and concentration of urine. Outcome. The primary analysis of this study was the ability of tubular markers to predict WRF. The outcome measure for this analysis was the first occurrence of WRF after the day of
JACC: Heart Failure Vol. 1, No. 5, 2013 October 2013:417–24
urine collection. Secondary outcome was the combined endpoint of the first occurrence of either death or HF hospitalization. The latter was defined as any hospitalization for HF induced by infection, supraventricular or ventricular arrhythmias, acute coronary syndromes, or renal dysfunction due to drug effects or worsening cardiac function. All events of this combined endpoint were centrally validated by an ad hoc committee blinded to study treatments. Statistical analysis. Data are given as mean SD when normally distributed, as median and interquartile range when distribution is skewed, and as frequencies and percentages for categorical variables. Student t test or Mann-Whitney U test was used to determine significant differences of variables between patients with and without WRF. We used a Cox proportional hazards model to estimate hazard ratios (HRs) with 95% CI for the occurrence of WRF. In multivariable analysis, all univariately associated variables were introduced in a multivariable model. Interaction terms with p value
Vol. 1, No. 5, 2013 ISSN 2213-1779/$36.00 http://dx.doi.org/10.1016/j.jchf.2013.05.007
Tubular Damage and Worsening Renal Function in Chronic Heart Failure Kevin Damman, MD, PHD,* Serge Masson, PHD,y Hans L. Hillege, MD, PHD,*z Adriaan A. Voors, MD, PHD,* Dirk J. van Veldhuisen, MD, PHD,* Patrick Rossignol, MD, PHD,x Gianni Proietti, MD,k Savino Barbuzzi, MD,{ Gian Luigi Nicolosi, MD,# Luigi Tavazzi, MD,** Aldo P. Maggioni, MD,yy Roberto Latini, MDy Groningen, the Netherlands; Milan, Terni, Venosa, Pordenone, Cotignola, and Florence, Italy; and Nancy, France Objectives
This study sought to investigate the relationship between tubular damage and worsening renal function (WRF) in chronic heart failure (HF)
Background
WRF is associated with poor outcome in chronic HF. It is unclear whether urinary tubular markers may identify patients at risk for WRF.
Methods
In 2,011 patients with chronic HF, we evaluated the ability of urinary tubular markers (N-acetyl-beta-Dglucosaminidase (NAG), kidney injury molecule (KIM)-1, and neutrophil gelatinase-associated lipocalin (NGAL) to predict WRF. Finally, we assessed the prognostic importance of WRF.
Results
A total of 290 patients (14.4%) experienced WRF during follow-up, and WRF was a strong and independent predictor of all-cause mortality and HF hospitalizations (hazard ratio [HR]: 2.87; 95% CI: 2.40 to 3.43; p < 0.001). Patients with WRF had lower baseline glomerular filtration rate and higher KIM-1, NAG, and NGAL levels. In a multivariableadjusted model, KIM-1 was the strongest independent predictor of WRF (HR: 1.23; 95% CI: 1.09 to 1.39 per log increase; p ¼ 0.001).
Conclusions
WRF was associated with strongly impaired outcome in patients with chronic HF. Increased level of urinary KIM-1 was the strongest independent predictor of WRF and could therefore be used to identify patients at risk for WRF and poor clinical outcome. (GISSI-HF–Effects of n-3 PUFA and Rosuvastatin on Mortality-Morbidity of Patients With Symptomatic CHF; NCT00336336) (J Am Coll Cardiol HF 2013;1:417–24) ª 2013 by the American College of Cardiology Foundation
Renal dysfunction, one of the most common and most important comorbidities in chronic heart failure (HF) is associated with unfavorable outcome, including mortality. Additionally, the development of worsening renal function (WRF) further impairs clinical outcome, including mortality and HF hospitalizations (1,2). Therefore, identifying patients at risk for WRF might lead to better use of life-saving therapies, less frequent hospital visits, and maybe even improved outcome.
Recently, more interest has been shown in markers of tubular injury than serum creatinine because these markers are more sensitive and specific to early changes in renal function, whereas serum creatinine is slowly affected and is dependent on muscle mass and age. We recently showed
From the *Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; yDepartment of Cardiovascular Research, IRCCS - Istituto di Ricerche Farmacologiche “Mario Negri”, Milan, Italy; zDepartment of Epidemiology, University Medical Center Groningen, Groningen, the Netherlands; xINSERM, Centre d’Investigations Cliniques, and Université de Lorraine, INSERM U961, Nancy, France; kUO Cardiologia Territoriale, Ospedale di Terni, Terni, Italy; {Servizio di Cardiologia, Ospedale di Venosa, Venosa, Italy; #Azienda Ospedaliera Santa Maria degli Angeli, UO Cardiologia, Pordenone, Italy; and the **GVM Care and Research, Ettore Sansavini Health Science Foundation–Maria Cecilia Hospital, Cotignola, Italy; and the yyANMCO Research Center, Florence, Italy. The GISSI-HF trial is endorsed by the Associazione Nazionale Medici Cardiologi Ospedalieri, Florence, Italy, Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy,
and Consorzio Mario Negri Sud, Santa Maria Imbaro, Italy. SPA, Pfizer, Sigma Tau, and AstraZeneca contributed to fund the main study. AstraZeneca provided separate support for the microalbuminuria substudy. Drs. Masson, Maggioni, and Latini received institutional grants from AstraZeneca, SPA, Sigma Tau, and Pfizer. Dr. Maggioni received honoraria for lectures from AstraZeneca. Dr. Tavazzi served on the speakers bureaus for the companies that financed the GISSI-HF trial. Dr. van Veldhuisen received board membership fees from Vifor, Amgen, BG Medicine, Johnson & Johnson, and Sorbent. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Manuscript received March 4, 2013; revised manuscript received April 29, 2013, accepted May 3, 2013.
See page 425
418
Damman et al. Tubular Damage and Worsening Renal Function
that these tubular damage markers confer excess risk in patients with chronic HF (3). eGFR = estimated However, the hypothetical glomerular filtration rate potential of these markers to HF = heart failure predict occurrence of deterioraKIM = kidney injury molecule tion of renal function over time NAG = N-acetyl-beta-Dhas not been evaluated in glucosaminidase patients with chronic HF. NGAL = neutrophil In the present substudy of the gelatinase-associated GISSI-HF (Gruppo Italiano per lipocalin lo Studio della Sopravvivenza WRF = worsening renal Nell’Infarto Miocardico) trial, we function set out to determine the prevalence of WRF, predictors of the occurrence of WRF and clinical significance of tubular markers in predicting WRF. Abbreviations and Acronyms
Methods The design and main results of the GISSI-HF trial have been described in detail elsewhere (4,5). The institutional review committee at each participating center approved the study, and all patients gave informed consent. A total of 2,130 patients provided a first-morning spot urine at any of the clinical visits scheduled in the trial. The mean time to urine sampling from randomization date in the trial was 1.2 years (range 0 to 3.5 years). Urine samples were stored at 70 C before analysis. Assessment of renal function, WRF, and tubular markers. Serum creatinine was measured, per protocol, at all clinical visits in local laboratories. Glomerular filtration rate (eGFR) (ml/min/1.73 m2) was estimated using the simplified modification of diet in renal disease formula. Baseline GFR was set at the time of urine collection. WRF was defined as 0.3 mg/dl and 25% increase in serum creatinine at any moment during follow-up. For sensitivity analysis, a reduction in eGFR >20% and an absolute increase >0.3 mg/dl in creatinine (both separately) were also considered. N-acetyl-beta-D-glucosaminidase (NAG), kidney injury molecule (KIM)-1, and neutrophil gelatinase-associated lipocalin (NGAL) levels were determined in urine (3). In short, NGAL was determined by means of a commercially available enzyme-linked immunosorbent assay (ELISA) kit from Antibody Shop (Gentofte, Denmark). NGAL was expressed in ng/ml (limit of detection 0.093 ng/ml). The enzymatic activity of NAG was evaluated using the substrate p-nitrophenyl N-acetyl-beta-D-glucosaminide (Sigma, St. Louis, Missouri; limit of detection 0.113 U/ml). Urinary KIM-1 measurements were performed using an ELISA (R&D Systems, Minneapolis, Minnesota; limit of detection 0.125 ng/ml). All urinary tubular marker concentrations were normalized to urinary creatinine concentrations to allow for correction for dilution and concentration of urine. Outcome. The primary analysis of this study was the ability of tubular markers to predict WRF. The outcome measure for this analysis was the first occurrence of WRF after the day of
JACC: Heart Failure Vol. 1, No. 5, 2013 October 2013:417–24
urine collection. Secondary outcome was the combined endpoint of the first occurrence of either death or HF hospitalization. The latter was defined as any hospitalization for HF induced by infection, supraventricular or ventricular arrhythmias, acute coronary syndromes, or renal dysfunction due to drug effects or worsening cardiac function. All events of this combined endpoint were centrally validated by an ad hoc committee blinded to study treatments. Statistical analysis. Data are given as mean SD when normally distributed, as median and interquartile range when distribution is skewed, and as frequencies and percentages for categorical variables. Student t test or Mann-Whitney U test was used to determine significant differences of variables between patients with and without WRF. We used a Cox proportional hazards model to estimate hazard ratios (HRs) with 95% CI for the occurrence of WRF. In multivariable analysis, all univariately associated variables were introduced in a multivariable model. Interaction terms with p value
