Prognostic value of plasma renin activity in heart failure patients with chronic kidney disease

International Journal of Cardiology 167 (2013) 711–715

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International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard

Prognostic value of plasma renin activity in heart failure patients with chronic kidney disease Roberta Poletti a,⁎, Giuseppe Vergaro a, Luc Zyw a, Concetta Prontera a, Claudio Passino a, b, Michele Emdin a a b

Division of Cardiovascular Medicine, Fondazione G. Monasterio, CNR-Regione Toscana, Via Giuseppe Moruzzi 1, 56124 Pisa, Italy Scuola Superiore Sant'Anna, Pisa, Italy

a r t i c l e

i n f o

Article history: Received 8 December 2011 Received in revised form 25 January 2012 Accepted 3 March 2012 Available online 28 March 2012 Keywords: Chronic heart failure Chronic kidney disease Plasma renin activity Renin–angiotensin system Natriuretic peptides

a b s t r a c t Background: Impairment of kidney function is frequently observed in chronic heart failure (CHF). It correlates with clinical and neurohormonal status, and affects prognosis. We aimed to identify the prognostic impact of plasma renin activity (PRA) in patients affected by CHF with chronic kidney disease (CKD). Methods: We enrolled 996 consecutive CHF patients (age 65 ± 13 years, mean ± SD, left ventricular ejection fraction, LVEF, 33 ± 10%), who underwent a complete clinical and neurohormonal characterization and were then followed-up (median 36 months) for the end point of cardiac death. Results: A stage ≥3 CKD (estimated glomerular filtration rate b 60 mL/min/1.73 m2) was found in 437 patients. Impaired renal function was associated with worse symptoms, lower LVEF, higher plasma norepinephrine, NTproBNP and PRA (all p b 0.001). As compared to patients with preserved renal function, those with CKD had higher cardiac mortality [106 (24%) vs 53 (9.5%), p b 0.001]. In CKD patients, at Cox multivariate analysis, only ejection fraction (HR 0.91, 95% CI 0.84–0.97, p = 0.008), NT-proBNP (2.53, 1.45–4.41, p = 0.001) and PRA (1.73, 1.16–2.58, p = 0.007) were independent predictors of cardiac death. ROC analysis identified a cut-off value for PRA of 3.29 ng/mL/h that predicted prognosis with the greatest accuracy. Finally, the elevation of both NT-proBNP and PRA identified a subset of patients with the highest risk of cardiac death. Conclusions: PRA has an independent prognostic value in CHF patients with CKD comorbidity. The combination of PRA and NT-proBNP identifies a group of high risk patients, who might benefit of a more intensive care, targeted to enhance renin–angiotensin system antagonism. © 2012 Elsevier Ireland Ltd. All rights reserved.

1. Introduction The activation of neurohormonal axes, in particular of the renin– angiotensin–aldosterone system (RAAS) as a maladaptive response to cardiac dysfunction, plays a key role in the evolution and outcome of chronic heart failure (CHF) [1–4]. Long-term survival in this syndrome remains poor despite the use of up-to-date pharmacological and device treatment, including RAAS antagonist drugs [5,6]. CHF and chronic kidney disease (CKD) share common risk factors and pathophysiological pathways, such as atherosclerosis, hypertension, neuroendocrine activation, endothelial dysfunction and inflammation. Indeed, a concomitant impairment of renal function is frequently observed in CHF patients, finally resulting in the “cardiorenal syndrome” [7], and is a strong predictor of morbidity and mortality [8–11]. RAAS is also activated in primary CKD [12] and accelerates progression of nephropathy [13]. Furthermore, chronic renal hypoperfusion together with an increase in sympathetic outflow, may enhance

⁎ Corresponding author. Tel.: + 39 0503152190; fax: + 39 0503152109. E-mail address: [email protected] (R. Poletti). 0167-5273/$ – see front matter © 2012 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2012.03.061

RAAS activation in patients with concomitant CKD and CHF, in an attempt to preserve renal function and to sustain cardiac output. Nevertheless, despite the huge amount of experimental evidences on the role of RAAS in the progression of end-organ damage, and the potential availability of novel therapeutical strategies of RAAS antagonism, there are currently limited data concerning its implications on selection of high-risk patients. Therefore, we aimed to assess the prognostic value of plasma renin activity (PRA), as an index of RAAS activation, in CHF patients with CKD on optimal medical treatment. 2. Materials and methods 2.1. Patients and study design The present report refers to a subanalysis of a study previously published by our group [6]. Between June 2002 and November 2008, we prospectively enrolled 996 consecutive patients with left ventricular systolic dysfunction (left ventricular ejection fraction, LVEF b50%), referred to our Division for CHF management, as previously described in detail [6]. Acute coronary syndrome within 6 months before the enrolment was the only exclusion criterion. All patients were receiving maximum tolerated dose of beta-blockers, ACE-inhibitors/angiotensin receptor blockers (ARBs) and aldosterone antagonists and instructed to limit daily dietary sodium intake (b4 g NaCl). All patients underwent clinical and humoral evaluation at study entry that included

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blood chemistry, NT-proBNP (by ECLIA, Elecsys® 2010 analyzer, Roche Diagnostics), catecholamines (by HPLC HCL-725 CA, Tosoh Corporation, Japan), PRA and aldosterone (by RIA, DiaSorin S.r.l., Saluggia, Italy), on blood withdrawn at 8 a.m. after a 30-minute rest in the supine position, as previously described in detail [6,14]. A two-dimensional Doppler echocardiographic study was performed in all patients. The study protocol was performed according to the Declaration of Helsinki, was approved by the Institutional Ethics Committee and written informed consent was obtained from all subjects. 2.2. Assessment of renal function Glomerular filtration rate (eGFR) was estimated by the Cockroft–Gault equation [15,16]: eGFR = [(140 − age in years) × (body weight in kg)] (×0.85 in women) / (72 × serum creatinine in mg/dL); in women, the value was multiplied by a corrective factor of 0.85. This formula has been validated in CHF and CKD settings, showing a correlation of 0.90 with accurate measures of GFR [17]. We used a cut-off value of eGFRb 60 mL/min/1.73 m2 to define renal dysfunction (stage 3 or greater, in particular), in accordance with current guidelines [18,19]. 2.3. Follow-up

confirmed with the Kolmogorov–Smirnov test. Univariate and multivariate survival analyses were performed with the Cox proportional hazard regression analysis. Continuous variables (age, body mass index, LVEF, TSH, fT3, fT4, C-reactive protein, creatinine, eGFR, haemoglobin, NT-proBNP, norepinephrine, PRA, aldosterone) and dichotomic variables (gender, atrial fibrillation, diabetes, ischaemic versus non-ischaemic aetiology, NYHA functional class I–II versus III–IV, pharmacological treatment) were entered into the Cox proportional hazard regression model to identify univariate predictors of cardiac mortality. All variables found to be significant at univariate analysis were then entered into multivariate model. The optimal cut-points for PRA and NT-proBNP were quantified using receiver operating characteristic curve (ROC) analysis, as the point of ROC corresponding to the maximum sum of specificity and sensitivity. Prognostic value of the spectrum of PRA levels was assessed with the P-spline method fitting data to a set of spline basis functions with a reduced set of knots, combined with the roughness penalty of smoothing splines. The Kaplan–Meier life table for cardiac mortality was used to analyze follow-up in the patient population. Differences in survival curves were studied using the log-rank test (Mantel–Cox). A P-value less than 0.05 was considered to be statistically significant.

3. Results

Follow-up started at the time of clinical examination and blood sampling and continued until study termination (April 2010). Independent interviewers obtained information directly from patients, relatives, Institute cardiologists or general practitioners in charge of the patient, regarding the date and cause of death. The primary end-point was cardiac death. Patients who died for noncardiac causes or underwent heart transplantation or ventricular assistance device implantation were considered censored at the time of the event. 2.4. Statistical analysis Statistical analysis was carried out using SPSS 16.0 (SPSS inc., Chicago, Il, USA). Data are expressed as mean ± standard deviation for normally distributed variables and as median and 25th–75th percentile for non-normally distributed variables. Differences between two groups were evaluated with Student's t-test for continuous variables and Pearson's Chi-square test for categorical variables. The ANOVA test with F statistics was performed to assess differences between more than two groups. Logtransformed values of original data were used in regression statistical analyses for continuous variables (e.g., NT-proBNP, epinephrine, norepinephrine, PRA, aldosterone) known to have a lognormal distribution. Normal distribution of variables was

Baseline characteristics of the overall population and of the subgroups divided according to renal function are shown in Table 1. Reduced renal function (eGFR b 60 mL/min/1.73 m2) was detected in 437 patients (44%), and was associated with worse symptoms, lower LVEF, higher incidence of ischaemic aetiology, diabetes and atrial fibrillation. Moreover, CKD patients also showed higher plasma levels of norepinephrine, NT-proBNP, PRA, aldosterone, as well as lower triiodothyronine. Notably, as compared to those with preserved renal function, patients with CKD received less frequently ACE-inhibitors or ARBs and were prescribed more often digoxin and diuretics. Interestingly, an increasing neurohormonal activation mirrored the progressive reduction in renal function (Table 2). During a median follow-up of 36 months (range 0–72), 273 deaths occurred. One-hundred and fifty-nine patients died due to cardiovascular causes (121 worsening CHF, 25 sudden deaths; 7, 3, 2 and 1

Table 1 Baseline demographic and clinical characteristics, as well as neurohormones concentrations in total cohort and in groups without or with chronic kidney disease (CKD), i.e stage ≥ 3 (eGFR b 60 mL/min/1.73 m2) of renal dysfunction.

Age (years) Gender (females/males %) Body mass index (kg/m2) LV ejection fraction (%) NYHA class I–II/III–IV (%) ICM, n (%) Atrial fibrillation, n (%) Creatinine (mg/dL) eGRF (mL/min/1.73 m2) Potassium (mmol/L) Sodium (mmol/L) C-reactive protein (mg/dL) Haemoglobin (g/dL) Diabetes, n (%) History of hypertension, n (%) ACEi/ARBs, n (%) Beta-blockers, n (%) Spironolactone, n (%) Digoxin, n (%) Furosemide, n (%) NT-proBNP (ng/L) PRA (ng/ml/h) Aldosterone (ng/L) Epinephrine (ng/L) Norepinephrine (ng/L) fT3 (ng/L) fT4 (ng/L) TSH (mUI/mL)

Total

No CKD

CKD

CKD vs no CKD

n = 996

N = 559

n = 437

P value

65 ± 13 75/25 26.6 ± 4.8 33 ± 10 62/38 433 (43) 169 (17) 1.25 ± 0.5 70.5 ± 34 4.07 ± 0.5 138.7 ± 2.9 1.19 ± 2.99 13.5 ± 1.7 271 (27) 471 (47) 820 (82) 805 (81) 591 (59) 313 (31) 714 (72) 1328 (467–3384) 1.6 (0.5–5) 142 (86–218) 31 (14–52) 567 (386–841) 2.4 ± 0.9 12.9 ± 5.2 1.6 (1–3)

59 ± 12 80/20 28.1 ± 5 34 ± 5 75/25 201 (36) 73 (13) 0.98 ± 0.2 92.9 ± 29 4.01 ± 0.5 138.7 ± 2.8 0.88 ± 0.94 14 ± 1.6 145 (26) 245 (44) 492 (88) 464 (83) 324 (58) 156 (28) 363 (65) 757 (305–1580) 1.38 (0.4–4.1) 138 (85–211) 30 (11–46) 481 (330–706) 2.6 ± 1 12.5 ± 4.7 1.5 (0.9–2.7)

73 ± 9 69/31 24.8 ± 4 30 ± 7 83/17 232 (53) 96 (22) 1.57 ± 0.6 42 ± 11 4.1 ± 0.6 138.6 ± 3.2 1.56 ± 3.85 13 ± 1.8 126 (29) 226 (52) 328 (75) 341 (78) 267 (61) 157 (36) 351 (80) 2947 (1454–7203) 2.0 (0.6–9.4) 153 (86–232) 35 (18–61) 665 (480–986) 2.2 ± 0.8 13.4 ± 5.7 1.8 (0.9–3.2)

0.001 0.001 0.001 0.001 0.001 0.0001 0.001 0.001 0.001 0.001 NS 0.0001 0.001 NS 0.01 0.0001 NS NS 0.006 0.0001 0.001 0.001 0.05 0.001 0.001 0.001 0.01 0.01

LV: left ventricular; NYHA: New York Heart Association; ICM: ischaemic cardiomyopathy; eGRF: estimated glomerular filtration rate by Cockroft–Gault formula; ACEi: angiotensin converting enzyme inhibitors; ARBs: angiotensin receptor blockers; NT-proBNP: aminoterminal fragment of pro-brain natriuretic peptide; PRA: plasma renin activity; fT3: free triiodothyronine; fT4: free tetraiodothyronine; TSH: thyroid stimulating hormone. Values are expressed as mean ± SD for normally distributed variables, and as median (25th– 75th percentile) for non-normally distributed variables.

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Table 2 Neurohormonal activation in subsets divided according to kidney function. F and P values were obtained from ANOVA analysis.

NT-proBNP (ng/L) PRA (ng/mL/h) Aldosterone (ng/L) Epinephrine (ng/L) Norepinephrine (ng/L)

eGFR ≥90 mL/min

eGFR 60–89 mL/min

eGFR 30–59 mL/min

eGFR b 29 mL/min

F

P

456 1.17 129 27 411

1022 1.27 137.4 28 472.5

2402 1.79 152 34 619

5076 2.69 225 36 797

141.8 9.3 4.8 9.9 46.1

b0.001 b0.001 b0.001 b0.001 0.003

(1701–1105) (0.4–4.0) (85–198) (10–47) (283–575)

(455–2219) (0.3–8.1) (83–210) (10–46) (307–657)

(1147–6068) (0.5–13.4) (86–244) (17–60) (432–966)

(2601–12074) (1.4–8.2) (109–332) (20–62) (508–1369)

eGFR: estimated glomerular filtration rate by the Cockroft–Gault equation, NT-proBNP: aminoterminal fragment of pro-brain natriuretic peptide; PRA: plasma renin activity.

secondary to acute myocardial infarction, stroke, endocarditis and pulmonary embolism, respectively). At 6-year follow up, patients with reduced eGFR showed higher cardiovascular mortality compared to those with eGFR > 60 mL/min/1.73 m 2 [106 (24%) vs 53 (9.5%), log rank 59.1, p b 0.001] (Fig. 1). When multivariable analysis was performed using univariate predictors of cardiovascular mortality in the subgroup with reduced eGFR, only NT-proBNP, PRA, and LVEF were independently related to outcome (Table 3), similar to what was previously found in the whole population [6]. According to the ROC cut-off points for NT-proBNP and PRA in predicting cardiac mortality (3635 ng/L and 3.29 ng/mL/h, respectively), patients with CKD were divided into four groups: low NT-proBNP/low PRA (n = 152); low NT-proBNP/high PRA (n = 101); high NT-proBNP/ low PRA (n = 104); high NT-proBNP/high PRA (n = 80). Patients with elevation of both biomarkers showed the highest risk of cardiac death, those with either high PRA or NT-proBNP showed an intermediate outcome, while the subset with both markers below the ROC cut-points presented the lowest rate of events (survival: 82%, 62%, 51%, 14%, respectively; all differences: p b 0.001). Comparisons among Kaplan–Meier curves are shown in Fig. 2. Interestingly, as concerns the prognostic role of PRA, P-spline analysis showed a progressive increase of risk for cardiac mortality (hazard ratio > 1) for PRA level > 2 ng/ml/h, with an abrupt increase after the cut-point identified by ROC-analysis (i.e. 3.29 ng/ml/h), as depicted in Fig. 3.

Fig. 1. Kaplan–Meier survival curves in the cohort of 996 chronic heart failure patients, according to eGRF ≥ 60 mL/min/1.73/m2 (no CKD) or b60 mL/min/1.73 m2 (CKD). Logrank statistic: 59.1; p b 0.0001.

4. Discussion The present study shows that significant CKD is present in 44% of patients with systolic CHF, and is associated with enhanced activation of adrenergic and RAAS systems and of cardiac endocrine function, as compared to patient with CHF and preserved renal function. In addition, patients with CKD show poorer prognosis, despite optimal medical treatment. Finally, in CHF and CKD patients, PRA and NT-proBNP, together with LVEF, are independently associated with prognosis and appear to provide additive prognostic information. Traditionally, renal contribution to CHF has been considered an adaptive response mechanism, characterized by a compensatory neurohormonal activation, including activation of the RAAS and enhanced adrenergic drive, with a vasoconstrictor and water/sodium-retentive action, aimed to expand the inadequate arterial blood volume, sustain arterial pressure, and maintain perfusion to vital organs [20]. At kidney level, however, the RAAS activation – also through an intrarenal production of angiotensin II [12] – is primarily aimed to preserve GFR, as renal blood flow decreases and renal perfusion pressure declines [21]. Although these pathways are initially beneficial in the context of a reduced cardiac output, in the long term they progressively contribute to worsen renal function and cardiovascular remodelling. Eventually, one may postulate that RAAS activation, favouring vascular remodelling/fibrosis of the heart and kidneys, further promotes cardiac and renal dysfunction, thus impacting negatively on prognosis. The assay of plasma B-type natriuretic peptide concentration has an established diagnostic and prognostic role, not only in CHF [22], but also in CKD patients [23,24], in whom the elevation of BNP/NTproBNP is not simply related to a reduced clearance, but also reflects the coexistence of heart disease/overload. The combination of NTproBNP and eGFR (as an estimate of renal function) better predicts short-term outcome in acute heart failure than either parameter alone [24]. In the present study, among a number of neurohormonal indices (exploring cardiac endocrine function, the sympathetic nervous system, the adrenal and thyroid function), only PRA, together with NT-proBNP, was independently associated with adverse outcome in patients with combined CHF and CKD. Our results are consistent with previous studies [5,6,25], showing that PRA is a strong prognosticator in CHF patients, and extends this observation to CHF patients with CKD. In this setting, the evidence that patients with both high NT-proBNP and high PRA showed a worse outcome compared to those with only NT-proBNP elevation, supports the concept that PRA provides additive prognostic information in this subset of patients. Recently, Szymanski and colleagues [26] demonstrated that active plasma renin concentration is an independent prognostic marker in a small cohort of CHF patients with impaired renal function. Our study extends this observation in a much larger CHF population, in which a wider panel of clinical and neurohormonal data was evaluated. Among all variables, those independently associated with worse prognosis – EF, NT-proBNP, PRA – might reflect different pathophysiological pathways of disease progression: i.e. extent of cardiac damage and severity of LV systolic dysfunction, myocyte stress, and RAAS activation (as determined by either impaired haemodynamics, or

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Table 3 Univariate and multivariate analyses of predictors for cardiac mortality. Variable

Odds ratio (95% CI)

NYHA class LV ejection fraction C-reactive protein Haemoglobin eGFR Cortisol γ-glutamyltransferase NT–proBNP Plasma renin activity Epinephrine Norepinephrine ACEi/ARBs

Univariate model 2.792 (1.803–4.324) 0.946 (0.925–0.967) 1.072 (1.029–1.118) 0.842 (0.751–0.944) 0.962 (0.946–0.978) 1.004 (1.002–1.005) 1.476 (1.177–1.852) 2.215 (1.833–2.676) 1.382 (1.205–1.584) 1.703 (1.373–2.112) 1.707 (1.232–2.367) 0.546 (0.361–0.826)

P value

Odds ratio (95% CI)

P value

b0.0001 b0.0001 0.0001 0.003 b0.0001 b0.001 b0.001 b0.0001 b0.0001 b0.0001 b0.001 0.004

Multivariate model – 0.905 (0.840–0.975) – – – – – 2.530 (1.451–4.412) 1.733 (1.163–2.581) – – –

– 0.008 – – – – – b 0.001 0.007 – – –

LV: left ventricular; NYHA: New York Heart Association; eGRF: estimated glomerular filtration rate by Cockroft–Gault formula; ACEi: angiotensin converting enzyme inhibitors; ARBs: angiotensin receptor blockers; NT-proBNP: aminoterminal fragment of pro-brain natriuretic peptide.

renal insufficiency), respectively, each contributing to further define patients' risk. Owing to the loss of functioning nephrons, CKD is associated per se with activation of RAAS system [27,12] and subsequent increase in PRA [28], irrespective of the presence of left ventricular dysfunction. RAAS effectors have been demonstrated to elicit inflammation and oxidative stress within the kidney, thus promoting fibrosis (particularly at the glomerular and tubular-interstitial level) and organ disease progression [29]. Indeed, in the CKD setting, ACE-inhibitors and ARBs are currently recommended as a first-line therapy to slow the progression of renal impairment [30–32]. However, in several studies [33–35] patients on chronic treatment with ACE-inhibitors and/or ARBs have been shown to exhibit a reflex increase in renin and angiotensin I (via a negative feedback loop). This phenomenon, together with the synthesis of RAAS effectors via alternative pathways

Fig. 2. Kaplan–Meier survival curves for cardiac mortality in four subgroups of CKD patients identified according to ROC optimal cut-off values of 3635 ng/L and 3.29 ng/mL/h for NT-proBNP and PRA, respectively. Low NT-proBNP/low PRA (A), low NT-proBNP/high PRA (B), high NT-proBNP/low PRA (C), high NT-proBNP/high PRA (D). Comparison among Kaplan–Meyer curves resulted statistically significant for A vs B and C (p = 0.025 and b 0.01, respectively), B vs C and D (p= 0.042 and b 0.0001, respectively), C vs D (pb 0.0001). Log-rank statistic: 77.8; p b 0.0001.

(e.g. chimases), may lead to ‘RAAS escape’, potentially limiting drug effectiveness. The reactive increase in RAAS effectors, such as angiotensin II and aldosterone, might thus explain why the prognostic value of PRA is well-maintained also in patients receiving ACEinhibitors or ARBs. The findings of the present study, therefore, highlight the need for further optimization of CHF medical therapy in patients exhibiting high levels of PRA and NT-proBNP, and should serve as a stimulus for the search of approaches to RAAS blockade, alternative to conventional ones, which may induce additive benefit, particularly in the setting of combined CHF and CKD, where the RAAS is extremely activated. Such an alternative strategy could be represented by the combination of ACE-inhibitors and ARBs, as well as by the use of the direct renin antagonist aliskiren [36], which has been demonstrated to decrease PRA and aldosteronuria in CHF patients, thus providing an effective RAAS blockade. Further results are expected from ongoing large trials evaluating the effect on CHF prognosis of aliskiren, on top of background ACE-inhibitors/ARBs therapy. Finally, current experimental investigations are defining the value of aldosterone synthase inhibitors and chymase inhibitors as promising tools for RAAS blockade. A further perspective might be the evaluation of the prognostic value of PRA in CHF patients with preserved eGFR, but very early tubulo-interstitial injury, as assessed by novel biomarkers such as neutrophil gelactinase-associated lipocalin (NGAL) and kidney injury

Fig. 3. Plasma renin activity (PRA) P-spline hazard ratio plot for cardiac mortality. The curve shows an exponential behaviour with risk increasing for higher PRA. The vertical line indicates PRA value corresponding to the 3.29 ng/mL/h cut-point.

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