Heart failure and chronic kidney disease in a registry of internal medicine wards

European Geriatric Medicine 5 (2014) 307–313

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Research paper

Heart failure and chronic kidney disease in a registry of internal medicine wards G. Lupattelli a,*, G. Reboldi b, F. Paciullo a, G. Vaudo a, M. Pirro a, L. Pasqualini a, A. Nobili c, P.M. Mannucci d, E. Mannarino a, on behalf of the REPOSI Investigator a

Internal Medicine, Angiology and Arteriosclerosis Diseases, Department of Medicine, University of Perugia, Italy Internal Medicine and Endocrine and Metabolic Science, Department of Medicine, University of Perugia, Italy IRCCS–Istituto di Ricerche Farmacologiche ‘‘Mario Negri’’, Milan, Italy d Scientific Direction, IRCCS Ca’ Granda Maggiore Hospital Foundation, Milan, Italy b c

A R T I C L E I N F O

A B S T R A C T

Article history: Received 9 May 2014 Accepted 11 August 2014 Available online 16 September 2014

Background: The aim of the present study was to evaluate the association between heart failure (HF) and chronic kidney disease (CKD) in tertiary care centers using the clinical records of patients enrolled in internal medicine departments. Patients and methods: We used the clinical records of 1380 elderly patients to identify patients with a history of HF and CKD using admission ICD codes and glomerular filtration rate (GFR) formulas. Magnitude and strength of such associations were investigated by univariable and multivariable analysis. Results: Of the 1380 patients enrolled, 27.9% had HF (age 80  7, BMI 27  6 kg/m2) and 17.4% CKD (age 81  7, BMI 26.8  6 kg/m2). Both groups were significantly older (P < 0.0001) with BMI higher than the patients without those diagnosis (P < 0.02). Patients with a history of CKD showed higher non-fasting glycaemia (140  86 vs. 125  63 mg/dL, P < 0.001). CKD was significantly associated with HF (P < 0.0001). Patients with HF had an estimated GFR lower than patients without HF (P < 0.0001). Comorbidity and severity indices were significantly higher in subjects with HF (P < 0.0001) and CKD (P < 0.0001) than in those without. Multivariable analysis showed a significant association between HF and age (for five years increase OR 1.13, P < 0.009), BMI (for each 3 kg/m2 increase OR 1.15, P < 0.001), GFR (for each decrease of 10 mL/min increase OR 0.92, P < 0.002) and severity index (IS) (for each 0.25 units increase OR 1.43, P < 0.001). Conclusion: HF on admission is strongly associated with CKD, older age, BMI, and SI. These data focus the value of epidemiological studies such REPOSI in identifying and monitoring multimorbidity in elderly. ß 2014 Elsevier Masson SAS and European Union Geriatric Medicine Society. All rights reserved.

Keywords: Heart failure Elderly Chronic kidney disease REPOSI

1. Introduction HF is a very common complex syndrome representing the final outcome of the majority of cardiovascular diseases. In developed countries, approximately 1–2% of the adult population is suffering from HF, with an increasing prevalence in elderly [1,2]. Also CKD, Abbreviations: CKD, chronic kidney disease; HF, heart failure; GFR, glomerular filtration rate; ICD, International Classification of Diseases; SIMI, Italian Society of Internal Medicine; BMI, Body Mass Index; CIRS, Cumulative Illness Rating Scale; IS, Severity Index; IC, Comorbidity Index; CDK-EPI, Chronic Kidney Disease Epidemiology Collaboration; KDOQI, Kidney Disease Outcomes Quality Initiative; REPOSI, REgistro POliterapie Societa` Italiana di Medicina Interna. * Corresponding author. Internal Medicine, Angiology and Atherosclerosis, Department of Medicine, ‘‘Santa Maria della Misericordia’’ Hospital, Piazzale Menghini, Sant’Andrea delle Fratte, 06132 Perugia, Italy. Tel.: +39 075 5784023; fax: +39 075 5784022. E-mail address: [email protected] (G. Lupattelli).

due to its large distribution, is now considered one of the most important public health problems, with a prevalence of about 13% in US adult population [3], increased in elderly, and in patients with cardiovascular disease [4]. In Italy, the epidemiology of CKD in the general population was evaluated in studies from small geographical areas, such as GUBBIO study in 1983–1985 (2748 patients aged 25–74 years) and the INCIPE study in 2006 (6200 patients  40 years old). The Gubbio study showed a prevalence of CKD 3-5 stage of 5.7% in men and 6.2% in women, while in the INCIPE study only gave a total prevalence of CKD of 12.7% (13,2% in men, 12,2% in women) with a prevalence of stage  3 of 6,7% (6,5% in men, 6,9% in women) [5,6]. Among patients of INCIPE study authors found a greater prevalence of CKD in patients with diabetes, hypertension, and  80 years old patients [6]. It is likely that the increase in life expectancy will lead to an increased prevalence of both heart and renal failure in a foreseeable future. Several studies showed a close relationship between these two

http://dx.doi.org/10.1016/j.eurger.2014.08.005 1878-7649/ß 2014 Elsevier Masson SAS and European Union Geriatric Medicine Society. All rights reserved.

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syndromes [7,8]. Specifically, in the Second Prospective Randomized Study of Ipobamine on Mortality and Efficacy (PRIME-II study) GFR emerged as the major prognostic factor in patients with HF [7]. The heart and kidney are linked by neuro-hormonal and hemodynamic features, that when unbalanced can determine the ‘‘cardio-renal syndrome’’. This condition has a complex pathophysiologic background yielding several clinical entities, where acute or chronic dysfunction of one organ can induce acute or chronic dysfunction of the other. Data on the cardio-renal syndrome and/or the prevalence and incidence of HF and its relation with chronic renal disease are mainly derived from U.S. studies or from large multinational trials [9]. In our country, such informations in over-60 hospitalized patients are limited and sparse [10,11]. Therefore, the aim of the study was to estimate the prevalence of HF and its association with CKD in consecutive patients admitted to Internal Medicine departments. 2. Patients and methods One thousand three hundred and eighty patients included in the REgistro POliterapie Societa` Italiana di Medicina Interna REPOSI) 2010 from 66 Internal Medicine Departments (683 males and 697 females) all of them over sixty-five years old, were enrolled in the study in the period between April 2010 and January 2011. REPOSI is an independent research project born from the collaboration between SIMI and the Mario Negri Institute for Pharmacological Research, performed for the first time in 2008 (REPOSI 2008) and was subsequently repeated in 2010 (REPOSI 2010). The main purpose of this collaborative research project is to create a network/observatory of Internal Medicine departments for the recruitment, monitoring and study of elderly patients, estimating disease prevalence, the predictors of polypathology and polypharmacy and their impact on major clinical outcomes for this class of people. As already described [12–15] patients were recruited in a sequential manner, e.g. all new patients admitted within four different specific weeks (one per season), for a minimum of five patients per week; inclusion criteria in the study were age over 65 years and the acceptance with a signed informed consent. This study was approved by the local Ethics Committee on human research. For each patient the diagnosis formulated at the admission, and corresponding to the medical history, was reported and coded according to the ICD-9-CM (1997 version of the International classification of diseases, 9th revision, and clinical modification) [16].

For the purpose of this study, we identified patients with ICD codes at the entrance for congestive HF (428.x, 402.x, 416.x, 425.4, 425.5, and 425.9) and CKD (585.x, 586.x, 403.x, 404.x). For all patients renal function at entry was estimated from serum creatinine using the CKD-EPI formulas [17]. Other admission diagnoses were acquired through a list of 14 different items (one for each system: cardiovascular disease, hypertension, vascular disease, respiratory disease, ear nose and throat diseases, gastrointestinal disease, kidney and genito-urinary disease, metabolic disorders, musculoskeletal disorders, nervous disease) and a score from 1 to 5 was applied depending on the severity of the pathology (1 = absent: no impairment of organ/ system; 5 = very severe impairment of organ/treatment is urgent/ the prognosis is severe). Through these scores we calculated the CIRS-IS resulting from the first 13 categories scores arithmetic means (excluding the category of psychiatric/behavioral disease) and the ‘‘co morbidity index’’ (CIRS-CI), consisting in the number of categories in which we found a score higher than or equal to 3 (excluding the category of psychiatric/behavioral disease). 2.1. Statistical analysis We used the Student’s t-test to compare means and the Chi2 test to compare proportions. Unadjusted prevalence estimates were obtained form tabular data. Multivariable logistic regression analysis was performed to evaluate the strength of the association between history of HF upon admission and renal disease with adjustment for a pre-defined set of predictors including age, sex, BMI, CIRS-IS, co-morbidity CIRS-CI. To account for the multi-center nature of the REPOSI data, robust variance estimation was used in all regression models using the Huber-White sandwich estimator, which considers observations as independent across groups (the REPOSI centers in this case). Analyses were performed using SAS 9.3 (SAS Institute, Cary, NC, USA) and STATA 12.1 (Statacorp, College Station, Tx, US). Statistical significance was set at P < 0.05 two-tailed.

3. Results Table 1 shows the general features of REPOSI populations and the characteristics of patients with and without HF. Over 1380 patients enrolled in this study 633 of them were males (49.6%), 747 females (50.5%); mean age was 79  7.3 years.

Table 1 Demographic and clinical characteristics of the REPOSI population: all patients, patients with and without heart failure (HF).

Age (years) Female sex (%) Weight (kg) Height (cm) BMI (kg/m2) Waist (cm) Systolic BP (mmHg) Diastolic BP min (mmHg) Heart rate (bpm) Blood glucose (mg/dL) Total cholesterol (mg/dL) Serum creatinine (mg/dL) eGFR (mL/min/1.73 m2) Hemoglobin (g/dL) CKD by admission ICD-9-CM (%) Anemia by admission ICD-9-CM (%) CIRS Severity Index CIRS Co-morbidity Index

All patients n = 1380

Patients with HF n = 383

Patients without HF n = 991

P-value*

79.0 (7.3) 49.6 70.24 (15.2) 164.07 (8.8) 26.04 (5.2) 93.7 (15.3) 133.79 (22.1) 75.45 (12.1) 80.73 (16.2) 127.68 (67.7) 163.07 (45.9) 1.24 (0.9) 60.32 (24.2) 11.96 (2.3) 17.4 4.0 1.6 (0.3) 2.9 (1.74)

80.3 (7.3) 47.8 72.15 (16.4) 163.4 (9.5) 26.9 (5.9) 94.53 (16.4) 133.3 (23.9) 75.1 (12.8) 81.9 (16.9) 135.1 (77.6) 163.9 (44.2) 1.4 (1.0) 53.9 (23.8) 12.1 (2.2) 25.9 4.4 1.8 (0.3) 3.5 (1.71)

78.5 (7.32) 50.2 69.5 (14.7) 164.3 (8.5) 25.6 (4.9) 93.4 (14.8) 134.1 (21.7) 75.6 (11.7) 80.3 (15.8) 124.9 (63.3) 162.5 (46.5) 1.2 (0.9) 62.7 (23.) 11.9(2.3) 14.1 3.8 1.6 (0.3) 2.7 (1.7)

<0.0001 0.4116 0.0049 0.0856 <0.0001 0.2715 0.5416 0.5116 0.1052 0.0123 0.6349 0.0002 <0.0001 0.3547 <0.0001 0.6088 <0.0001 <0.0001

*P-values for the comparison of patients with HF vs. those without HF; BMI: body mass index; BP: blood pressure; eGFR: estimated glomerular filtration rate (4 variable CKD-EPI Equation); CKD: chronic kidney disease; ICD-9-CM: International Classification of Diseases Clinical Modification; CIRS: Cumulative Illness Rating Scale.

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Fig. 1. Age adjusted probability of HF on admission. Panel A: probability of HF by presence or absence of CKD as listed diagnosis. Panel B: probability of HF by admission eGFR as a continuous variable.

According to ICD codes, 383 (27.9%) had received a diagnosis of HF and the prevalence of ICD cases of CKD was 17.4% (239 patients). Among patients with HF, the percentage of subjects with stage 4-5K/DOQI was approximately doubled compared with patients without HF. In addition, among HF patients, blood glucose levels on admission were significantly higher (135  77.6 vs. 124.9  63.3 mg/dL, P = 0.01). On admission patients with HF had significantly higher serum creatinine levels (1.40  1.0 vs. 1.19  0.9 mg/dL, P = 0.0002) and significantly reduced values of eGFR (53.9  23.8 vs. 62.7  23.9 mL/min, P < 0.0001) than those without HF. Patients with history of renal failure on admission were significantly older (80.9  7.0 vs. 78.6  7.4, P < 0.0001) had an higher body weight (72.6  16.6 vs. 69.8  14.9 kg, P = 0.0093), a higher BMI (26.8  5.9 vs. 25.9  5.1 kg/m2, P = 0.0185) and

non-fasting glucose blood levels significantly higher (140  86 vs. 125  63 mg/dL, P < 0.001) and an increased waist circumference (95.5  15.5 vs. 93.3  15.2 cm, P = 0.0498) than patients without CKD. The prevalence of CKD was greater when calculated on the basis of the values of GFR obtained by CKD-EPI formulas and ICD codes: 451 patients, and of these only 224 had a prior history of renal disease. The age-adjusted probability of HF on admission was significantly higher (P < 0.0001) in patients with CKD defined by admission ICD (Fig. 1, panel A) and inversely related to the estimated e-GFR (P < 0.0001) (Fig. 1 panel B). The probability of HF increases progressively with increasing stage of CKD (K/DOKI) even if adjusted for age (Fig. 1 panel B) and with increasing grade of BMI whether adjusted or unadjusted for age (Fig. 2).

60

Age Adjusted Probability of HF, %

Undjusted Probability of HF, %

60

50

40

30

20

10

50

40

30

20

10 15

20

25

30

35

40

15

Body Mass Index, kg/m 2

20

25

30

35

Body Mass Index, kg/m 2

NKF-K/DOQI CKD Stage > 3 Absent

Present

Fig. 2. Probability of HF on admission as a function of BMI stratified by NKF-K/DOQI CDK Stage > 3.

40

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Relying on ICD-9-CM codes, the prevalence of anemia was extremely low (4.0%, for a total of 55 patients); on the contrary, using hemoglobin values on admission, the prevalence of anemia was definitely higher (55.1%). On admission, patients with a history of CKD had hemoglobin values significantly lower (11.3  2.3 vs. 12.1  2.3 g/dL, P < 0.0001). No significant association was observed between HF and the prevalence of anemia at admission. Comorbidity (CIRS_IC) and severity (CIRS_IS) indices were significantly increased in patients with HF (3.5 vs. 2.7, P < 0.0001 and 1.8 vs. 1.6, P < 0.0001) and in patients with CKD (3.9 vs. 2.7, P < 0.02 and 1.9 vs. 1.6, P < 0.0001) when compared with patients without HF and CKD respectively. The multivariable regression analysis showed an independent association between HF and age (for each increment of 10 years, the OR is 1.135, P = 0.009), BMI (for each increment of three units the OR is 1.146 P < 0.001), the comorbidity-severity index,(for each increment of 0.25 units the OR was 1.437, P < 0.001) and the reduction of GFR (for a reduction of 10 mlL/min/1.73 m2the OR was 1.091, P = 0.002). Conversely, the association between HF and previous diagnosis of CKD (with ICD-9-CM) was not significant (P = 0.08).

4. Discussion Our study underlined the well known relationship between the severity of kidney impairment and the risk of HF [18,19] (Fig. 1). Multivariate analysis showed that the risk of HF increases significantly with the progression of renal failure. For each decrease of 10 mL/min of filtrate, the OR is respectively 1.092 (P = 0.0021) using the CKD-EPI, and this independently from other factors such as age, BMI and IS. Also the bidirectional nature of cardio-renal syndrome, was highlighted in our series, in fact in patients with HF the percentage of Stage 4 and 5K/DOKI was approximately doubled compared to the others. Kidney disease is a powerful risk factor for the genesis and progression of HF; particularly, as described in the reno-cardiac syndrome which is now becoming one of the pre-eminent issues in public health [18,19], chronic failure triggers a series of changes in the neuroendocrine system, resulting in the progression of cardiovascular disease, increased water load, electrolyte imbalance, and inflammation, all of the mechanisms underlying the genesis of HF. In a recently published study of REPOSI data base, the prognostic value of the estimated glomerular filtration rate has been analyzed: a reduced glomerular filtration rate at admission was associated with in-hospital mortality while the decrease after discharge with death within three months [20]; moreover, in the same analysis those patients with a low GFR had a lower Barthel score, and a tendency towards cognitive impairment [20]. Another significant finding emerging from our analysis is related to general characteristics of patients with HF and renal failure. As expected, the group of patients with HF and those with renal failure were significantly older than the unaffected; the increased prevalence of those diseases with increasing age has already been documented by other studies [5]. Among the old hospitalized patients from Internal Medicine Wards we found an high prevalence of HF, higher than that showed by the previous REPOSI study [15] (27% vs. 14%). This could be ascribed to the difference in ICD codes: in REPOSI 2008 HF prevalence was calculated on the ICD-9 CM code 428, while we used six different ICD9-CM codes related to HF, thus including a higher group of people. CKD prevalence, calculated using ICD-9 CM codes, was 17.4%, while the prevalence of renal failure calculated on the basis of the values of GFRC (CKD-EPI formula) was 49%. Also other studies

showed an underestimation of CKD [21] in hospitalized adult patients. This can be explained by the fact that, even in cases where there is a documented evidence of renal failure, this is not always listed among the encodings ICD-9 CM. Even anemia, such as kidney failure, has previously been under diagnosed. In fact we found a prevalence of 4% using ICD9 CM codes while the prevalence using WHO criteria based on hemoglobin levels at the admission was 55.1%. In patients with a history of renal failure, we found significantly lower values of hemoglobin (P < 0.0001), but the same data has not been demonstrated in patients with HF. In addition to the increased age, patients with HF diagnosis on admission and patients with history of renal CKD had a significantly higher BMI than the other and significantly increased indices of co morbidity and severity. Also BMI was found to be an independent risk factor for HF (OR: 1.075, P = 0.0132). Obesity is considered to be an important risk factor for the genesis of HF through several mechanisms; the first one as an intermediate risk factor of metabolic syndrome, then leading to ischemic heart disease [22]. Furthermore, the prevalence of hypertension is three times higher among obese, facilitating the development concentric hypertrophy [23,24]; on the other hand the increase of circulating volume and consequently of preload favors the development of eccentric hypertrophy. Another link between obesity and HF could be related to the direct cardio toxicity of visceral fat. In fact is known that this kind of adipose tissue is able to produce several substances that may interact with the cardiovascular system. Among these, there are IL6 and TNF alpha that facilitate the onset of inflammation and insulin resistance [25]. The adipose tissue is also capable of releasing renin involved in the pathogenesis of hypertension and in cardiac remodeling, and plasminogen activator inhibitor (PAI) involved in the thrombotic process [25,26]. Also the obstructive sleep apnea syndrome, typically present in obese, through its consequences to the right sections may contribute to the development of HF [27–29]. In this study, there are several limitations. Firstly, we cannot know how and whether GFRC reduction may depend on a parenchimal kidney disease or on a pre-renal condition because we do not have GFR and we just considered creatinine values at the admission. The second limitation is that cross sectional design of the study does not allow interpreting the causal direction of HFCKD association; the third limitation is that the diagnosis based on ICD9 codes, in absence of other sources inferable from REPOSI minimum data sets, might be a bias in the estimation of disease prevalence.

5. Conclusions The main purpose of REPOSI project is to build up a single national database focusing on comorbidity and polytherapy in the elderly, mostly affected by several chronic diseases with frequent hospitalizations. The multicentricity and the independence of REPOSI, with the involvement of 66 centers belonging to 47 different Italian hospitals, are the main strengths of this study. In fact, it makes possible to obtain a representative sample of the elderly hospitalized in Italian Internal Medicine wards, a population often excluded from clinical trials. Each participating center has then the opportunity to perform an independent data analysis in order to develop different studies with several end-points on the same type of population. In this context, our study has been developed to define the characteristics of patients with HF and chronic renal failure highlighting the correlation between these two syndromes. BMI, age and comorbidity showed to influence the onset of HF.

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Disclosure of interest The authors declare that they have no conflicts of interest concerning this article.

Appendix A. Investigators and co-authors of the REPOSI (REgistro POliterapie SIMI, Societa` Italiana di Medicina Interna) Study Group are as follows: Steering Committee: Pier Mannuccio Mannucci (Chair, Fondazione IRCCS Ca` Granda Ospedale Maggiore Policlinico, Milano), Alessandro Nobili (co-chair, IRCCS-Istituto di Ricerche Farmacologiche ‘‘Mario Negri’’, Milano), Mauro Tettamanti, Luca Pasina, Carlotta Franchi (IRCCS-Istituto di Ricerche Farmacologiche ‘‘Mario Negri’’, Milano), Francesco Salerno (IRCCS Policlinico San Donato Milanese, Milano), Salvatore Corrao (ARNAS Civico, Di Cristina, Benfratelli, DiBiMIS, Universita` di Palermo, Palermo), Alessandra Marengoni (Spedali Civili di Brescia, Brescia), Alfonso Iorio (McMaster University, Hamilton, Canada), Maura Marcucci (McMaster University, Hamilton, Canada). Clincal data monitoring and revision: Eleonora Sparacio, Stefania Alborghetti, Rosa Di Costanzo (IRCCS-Istituto di Ricerche Farmacologiche ‘‘Mario Negri’’, Milano). Database Management and Statistics: Mauro Tettamanti, Codjo Djignefa Djade (IRCCS-Istituto di Ricerche Farmacologiche ‘‘Mario Negri’’, Milano). Investigators: Domenico Prisco, Elena Silvestri, Caterina Cenci, Tommaso Barnini (Azienda Ospedaliero Universitaria Careggi Firenze, SOD Patologia Medica); Giuseppe Delitala, Stefano Carta, Sebastiana Atzori (Azienda Mista Ospedaliera Universitaria, Sassari, Clinica Medica); Gianfranco Guarnieri, Michela Zanetti, Annalisa Spalluti (Azienda Ospedaliera Universitaria Ospedali Riuniti di Trieste, Trieste, Clinica Medica Generale e Terapia Medica); Maria Grazia Serra, Maria Antonietta Bleve (Azienda Ospedaliera ‘‘Cardinale Panico’’ di Tricase, Lecce, Unita` Operativa Complessa Medicina); Massimo Vanoli, Giulia Grignani, Gianluca Casella (Azienda Ospedaliera della Provincia di Lecco, Ospedale di Merate, Lecco, Medicina Interna); Laura Gasbarrone (Azienda Ospedaliera Ospedale San Camillo Forlanini, Roma, Medicina Interna 1); Giorgio Maniscalco, Massimo Gunelli, Daniela Tirotta (Azienda Ospedaliera Ospedale San Salvatore, Pesaro, Soc Medicina Interna); Antonio Brucato, Silvia Ghidoni, Paola Di Corato (Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Medicina 1); Mauro Bernardi, Silvia Li Bassi, Luca Santi (Azienda Ospedaliera Policlinico Sant’Orsola-Malpighi, Bologna, Semeiotica Medica Bernardi); Giancarlo Agnelli, Alfonso Iorio, Maura Marcucci, Emanuela Marchesini (Azienda Ospedaliera Santa Maria della Misericordia, Perugia, Medicina Interna e Cardiovascolare); Elmo Mannarino, Graziana Lupattelli, Pamela Rondelli, Francesco Paciullo (Azienda Ospedaliera Santa Maria della Misericordia, Perugia, Medicina Interna, Angiologia, Malattie da Arteriosclerosi); Fabrizio Fabris, Michela Carlon, Francesca Turatto (Azienda Ospedaliera Universita` di Padova, Padova, Clinica Medica I); Maria Cristina Baroni, Marianna Zardo (Azienda Ospedaliera Universita` di Parma, Parma, Clinica e Terapia Medica); Roberto Manfredini, Christian Molino, Marco Pala, Fabio Fabbian (Azienda Ospedaliera - Universitaria Sant’Anna, Ferrara, Unita` Operativa Clinica Medica); Ranuccio Nuti, Roberto Valenti, Martina Ruvio, Silvia Cappelli (Azienda Ospedaliera Universita` Senese, Siena, Medicina Interna I); Giuseppe Paolisso, Maria Rosaria Rizzo, Maria Teresa Laieta (Azienda Ospedaliera Universitaria della Seconda Universita` degli Studi di Napoli, Napoli, VI Divisione di Medicina Interna e Malattie Nutrizionali dell’Invecchiamento); Teresa Salvatore, Ferdinando Carlo Sasso (Azienda Ospedaliera Universitaria della Seconda Universita` degli Studi di

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Napoli, Napoli, Medicina Interna e Malattie Epato-Bilio Metaboliche Avanzate); Riccardo Utili, Emanuele Durante Mangoni, Daniela Pinto (Azienda Ospedaliera Universitaria della Seconda Universita` degli Studi di Napoli, Napoli, Medicina Infettivologica e dei trapianti); Oliviero Olivieri, Anna Maria Stanzial (Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Unita` Operativa di Medicina Interna B); Renato Fellin, Stefano Volpato, Sioulis Fotini (Azienda Ospedaliera Universitaria Ospedale Sant’Anna, Ferrara, Unita` Operativa di Medicina Interna Gerontologia e Geriatria); Mario Barbagallo, Ligia Dominguez, Lidia Plances, Daniela D’Angelo (Azienda Ospedaliera Universitaria Policlinico Giaccone Policlinico di Palermo, Palermo, Unita` Operativa di Geriatria e Lungodegenza); Giovanbattista Rini, Pasquale Mansueto, Ilenia Pepe (Azienda Ospedaliera Universitaria Policlinico P. Giaccone di Palermo, Palermo, Medicina Interna e Malattie Metaboliche); Giuseppe Licata, Luigi Calvo, Maria Valenti (Azienda Ospedaliera Universitaria Policlinico P. Giaccone di Palermo, Palermo, Medicina Interna e Cardioangiologia); Claudio Borghi, Enrico Strocchi, Elisa Rebecca Rinaldi (Azienda Ospedaliera Universitaria Policlinico S. Orsola-Malpighi, Bologna, Unita` Operativa di Medicina Interna Borghi); Marco Zoli, Elisa Fabbri, Donatella Magalotti (Azienda Ospedaliera Universitaria Policlinico S. Orsola-Malpighi, Bologna, Unita` Operativa di Medicina Interna Zoli); Alberto Auteri, Anna Laura Pasqui, Luca Puccetti (Azienda Ospedaliera Universitaria Senese, Siena, Medicina 3); Franco Laghi Pasini, Pier Leopoldo Capecchi, Maurizio Bicchi (Azienda Ospedaliera Universitaria Senese, Siena, Unita` Operativa Complessa Medicina 2); Carlo Sabba`, Francesco Saverio Vella, Alessandro Marseglia, Chiara Valentina Luglio (Azienda Ospedaliero-Universitaria Consorziale Policlinico di Bari, Bari, Medicina Interna Universitaria C. Frugoni); Giuseppe Palasciano, Maria Ester Modeo, Annamaria Aquilino, Pallante Raffaele (Azienda Ospedaliero-Universitaria Consorziale Policlinico di Bari, Bari, Medicina Interna Ospedale ‘‘Pende-Ferrannini’’); Stefania Pugliese, Caterina Capobianco (Azienda Ospedaliero-Universitaria Consorziale Policlinico di Bari, Bari, Clinica Medica I Augusto Murri); Alfredo Postiglione, Maria Rosaria Barbella, Francesco De Stefano (Azienda Ospedaliera Universitaria Policlinico Federico II di Napoli, Medicina Geriatrica Dipartimento di Clinica Medica); Luigi Fenoglio, Chiara Brignone, Christian Bracco, Alessia Giraudo (Azienda Sanitaria Ospedaliera Santa Croce e Carle di Cuneo, Cuneo, S. C. Medicina Interna); Giuseppe Musca, Olga Cuccurullo (Azienda Sanitaria Provinciale di Cosenza Presidio Ospedaliero di Cetraro, Cosenza, Unita` Operativa Complessa Medicina Interna); Luigi Cricco, Alessandra Fiorentini (COB Stabilimento Montefiascone, Viterbo, Unita` Operativa Complessa di Geriatria e Medicina); Maria Domenica Cappellini, Giovanna Fabio, Sonia Seghezzi, Margherita Migone De Amicis (Fondazione IRCCS Ca` Granda Ospedale Maggiore Policlinico, Milano, Unita` Operativa Medicina Interna IA); Silvia Fargion, Paola Bonara, Mara Bulgheroni, Rosa Lombardi (Fondazione IRCCS Ca` Granda Ospedale Maggiore Policlinico, Milano, Medicina Interna 1B); Fabio Magrini, Ferdinando Massari, Tatiana Tonella (Fondazione IRCCS Ca` Granda Ospedale Maggiore Policlinico, Milano, Unita` Operativa Medicina Cardiovascolare); Flora Peyvandi, Alberto Tedeschi, Raffaella Rossio (Fondazione IRCCS Ca` Granda Ospedale Maggiore Policlinico, Milano, Medicina Interna 2); Guido Moreo, Barbara Ferrari, Luisa Roncari (Fondazione IRCCS Ca` Granda Ospedale Maggiore Policlinico, Milano, Medicina Interna 3); Valter Monzani, Valeria Savojardo, Christian Folli, Maria Magnini (Fondazione IRCCS Ca` Granda Ospedale Maggiore Policlinico, Milano, Medicina d’Urgenza); Daniela Mari, Paolo Dionigi Rossi, Sarah Damanti, Silvia Prolo (Fondazione IRCCS Ca` Granda Ospedale Maggiore Policlinico, Milano, Geriatria); Maria Sole Lilleri (Fondazione IRCCS Ca` Granda Ospedale Maggiore Policlinico, Milano, Medicina Generale ad Indirizzo Geriatrico); Luigi Cricco, Alessandra Fiorentini (COB Viterbo, Stabilimento Montefiascone, Viterbo, UOC Geriatria e Medicina); Giuliana Micale (IRCCS Istituto Auxologico Italiano, Milano, Medicina Generale ad indirizzo Geriatrico); Mauro

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Podda, Carlo Selmi, Francesca Meda (IRCCS Istituto Clinico Humanitas, Milano, Clinica Medica); Francesco Salerno, Silvia Accordino, Alessio Conca, Valentina Monti (IRCCS Policlinico San Donato e Universita` di Milano, San Donato Milanese, Medicina Interna); Gino Roberto Corazza, Emanuela Miceli, Marco Vincenzo Lenti, Donatella Padula (IRCCS Policlinico San Matteo di Pavia, Pavia, Clinica Medica I, Reparto 11); Carlo L. Balduini, Giampiera Bertolino, Stella Provini, Federica Quaglia (IRCCS Policlinico San Matteo di Pavia, Pavia, Clinica Medica III); Giovanni Murialdo, Marta Bovio (IRCS Azienda Ospedaliera Universitaria San Martino-IST di Genova, Genova, Clinica di Medicina Interna 2); Franco Dallegri, Luciano Ottonello, Alessandra Quercioli, Alessandra Barreca (Universita` di Genova, Genova, Medicina Interna 1); Maria Beatrice Secchi, Davide Ghelfi (Ospedale Bassini di Cinisello Balsamo, Milano, Divisione Medicina); Wu Sheng Chin, Laura Carassale, Silvia Caporotundo (Ospedale Bassini, Cinisello Balsamo, Milano, Unita` Operativa di Geriatria); Luigi Anastasio, Lucia Sofia, Maria Carbone (Ospedale Civile Jazzolino di Vibo Valentia, Vibo Valentia, Medicina interna); Giancarlo Traisci, Lucrezia De Feudis, Silvia Di Carlo (Ospedale Civile Santo Spirito di Pescara, Pescara, Medicina Interna 2); Giovanni Davı`, Maria Teresa Guagnano, Simona Sestili (Ospedale Clinicizzato SS. Annunziata, Chieti, Clinica Medica); Elisabetta Bergami, Emanuela Rizzioli (Ospedale del Delta, Lagosanto, Ferrara, Medicina Interna); Carlo Cagnoni, Luca Bertone, Antonio Manucra (Ospedale di Bobbio, Piacenza, Unita` Operativa Medicina e Primo Soccorso); Alberto Buratti, Tiziana Tognin, Nicola Lucio Liberato (Azienda Ospedaliera della Provincia di Pavia, Ospedale di Casorate Primo, Pavia, Medicina Interna); Giordano Bernasconi, Barbara Nardo (Ospedale di Circolo di Busto Arsizio, Varese, Medicina I); Giovanni Battista Bianchi, Sabrina Giaquinto Ospedale ‘‘SS Gerosa e Capitanio’’ di Lovere, Bergamo, Unita` Operativa Complessa di Medicina Generale, Azienda Ospedaliera ‘‘Bolognini’’ di Seriate, Bergamo; Giampiero Benetti, Michela Quagliolo, Giuseppe Riccardo Centenaro (Ospedale di Melegnano, Vizzolo Predabissi, Melegnano, Medicina 1); Francesco Purrello, Antonino Di Pino, Salvatore Piro (Ospedale Garibaldi Nesima, Catania, Unita` Operativa Complessa di Medicina Interna); Gerardo Mancuso, Daniela Calipari, Mose` Bartone, Francesco Gullo (Ospedale Giovanni Paolo II Lamezia Terme, Catanzaro, Unita` Operativa Complessa Medicina Interna); Michele Cortellaro, Marina Magenta, Francesca Perego; Maria Rachele Meroni (Ospedale Luigi Sacco, Milano, Medicina 3˚); Marco Cicardi, Antonio Gidaro Marina Magenta (Ospedale Luigi Sacco, Milano, Medicina II); Andrea Sacco, Antonio Bonelli, Gaetano Dentamaro (Ospedale Madonna delle Grazie, Matera, Medicina); Renzo Rozzini, Lina Falanga, Alessandro Giordano (Ospedale Poliambulanza, Brescia, Medicina Interna e Geriatria); Paolo Cavallo Perin, Bartolomeo Lorenzati, Gabriella Gruden, Graziella Bruno (Dipartimento di Scienze Mediche, Universita` di Torino, Citta` della Scienza e della Salute, Torino, Medicina 3); Giuseppe Montrucchio, Elisabetta Greco, Pietro Tizzani (Dipartimento di Scienze Mediche, Universita` di Torino, Citta` della Scienza e della Salute, Torino, Medicina Interna 5); Giacomo Fera, Maria Loreta Di Luca, Donatella Renna (Ospedale San Giacomo di Monopoli, Bari, Unita` Operativa Medicina Interna); Antonio Perciccante, Alessia Coralli (Ospedale San Giovanni-Decollato-Andisilla, Civita Castellana Medicina); Rodolfo Tassara, Deborah Melis, Lara Rebella (Ospedale San Paolo, Savona, Medicina I); Giorgio Menardo, Stefania Bottone, Elsa Sferrazzo (Ospedale San Paolo, Savona, Medicina Interna e Gastroenterologia); Claudio Ferri, Rinaldo Striuli, Rosa Scipioni (Ospedale San Salvatore, L’Aquila, Medicina Interna Universitaria); Raffaella Salmi, Piergiorgio Gaudenzi, Susanna Gamberini, Franco Ricci (Azienda Ospedaliera-Universitaria S. Anna, Ferrara, Unita` Operativa di Medicina Ospedaliera II); Cosimo Morabito, Roberto Fava (Ospedale Scillesi d’America, Scilla Medicina); Andrea Semplicini, Lucia Gottardo (Ospedale SS. Giovanni e Paolo, Venezia, Medicina Interna 1); Giuseppe Delitala, Stefano Carta, Sebastiana Atzori (Ospedale Universitario Policlinico di Sassari, Sassari, Clinica

Medica); Gianluigi Vendemiale, Gaetano Serviddio, Roberta Forlano (Ospedali Riuniti di Foggia, Foggia, Medicina Interna Universitaria); Luigi Bolondi, Leonardo Rasciti, Ilaria Serio (Policlinico Sant’OrsolaMalpighi, Bologna, Unita` Operativa Complessa Medicina Interna); Cesare Masala, Antonio Mammarella, Valeria Raparelli (Policlinico Umberto I, Roma, Medicina Interna D); Filippo Rossi Fanelli, Massimo Delfino, Antonio Amoroso (Policlinico Umberto I, Roma, Medicina Interna H); Francesco Violi, Stefania Basili, Ludovica Perri (Policlinico Umberto I, Roma, Prima Clinica Medica); Pietro Serra, Vincenzo Fontana, Marco Falcone (Policlinico Umberto I, Roma, Terza Clinica Medica); Raffaele Landolfi, Antonio Grieco, Antonella Gallo (Policlinico Universitario A. Gemelli, Roma, Clinica Medica); Giuseppe Zuccala`, Francesco Franceschi, Guido De Marco, Cordischi Chiara, Sabbatini Marta (Policlinico Universitario A. Gemelli, Roma, Roma, Unita` Operativa Complessa Medicina d’Urgenza e Pronto Soccorso); Martino Bellusci, Donatella Setti, Filippo Pedrazzoli (Presidio Ospedaliero Alto Garda e Ledro, Ospedale di Arco, Trento, Unita` Operativa di Medicina Interna Urgenza/Emergenza); Giuseppe Romanelli, Caterina Pirali, Claudia Amolini (Spedali Civili di Brescia, Brescia, Geriatria); Enrico Agabiti Rosei, Damiano Rizzoni, Luana Castoldi (Spedali Civili di Brescia, Brescia, Seconda Medicina); Antonio Picardi, Umberto Vespasiani Gentilucci, Chiara Mazzarelli, Paolo Gallo (Universita` Campus Bio-Medico, Roma, Medicina Clinica-Epatologia); Luigina Guasti, Luana Castiglioni, Andrea Maresca, Alessandro Squizzato, Sara Contini, Marta Molaro (Universita` degli Studi dell’Insubria, Ospedale di Circolo e Fondazione Macchi, Varese, Medicina Interna I); Giorgio Annoni, Maurizio Corsi, Sara Zazzetta (Universita` degli studi di Milano-Bicocca Ospedale S. Gerardo, Monza, Unita` Operativa di Geriatria); Marco Bertolotti, Chiara Mussi, Roberto Scotto, Maria Alice Ferri, Francesca Veltri (Universita` di Modena e Reggio Emilia, AUSL di Modena, Modena, Nuovo Ospedale Civile, Unita` Operativa di Geriatria); Franco Arturi, Elena Succurro, Giorgio Sesti, Umberto Gualtieri (Universita` degli Studi Magna Grecia, Policlinico Mater Domini, Catanzaro, Unita` Operativa Complessa di Medicina Interna); Francesco Perticone, Angela Sciacqua, Michele Quero, Chiara Bagnato (Universita` Magna Grecia Policlinico Mater Domini, Catanzaro, Unita` Operativa Malattie Cardiovascolari Geriatriche); Paola Loria, Maria Angela Becchi, Gianfranco Martucci, Alessandra Fantuzzi, Mauro Maurantonio (Universita` di Modena e Reggio Emilia, Medicina Metabolica-NOCSAE, Baggiovara, Modena); Roberto Corinaldesi, Roberto De Giorgio, Mauro Serra, Valentina Grasso, Eugenio Ruggeri, Lorenzo Mauro Carozza, Fabio Pignatti (Dipartimento di Scienze Mediche e Chirurgiche, Unita` Operativa di Medicina Interna, Universita` degli Studi di Bologna/Azienda Ospedaliero-Universitaria S.Orsola-Malpighi, Bologna).

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