Risk Factors and Prognosis of Cardiorenal Syndrome Type 1 in Elderly Chinese Patients: A Retrospective Observational Cohort Study Open Access

Cardiorenal syndrome type 1 (CRS1) is a syndrome characterized by a rapid worsening of cardiac function leading to acute kidney injury (AKI), causing high mortality rates, substantial loss in quality of life and high healthcare costs [1,2,3]. Elderly patients often have one or more comorbidities such as hypertension, diabetes, anaemia, chronic obstructive pulmonary disease or chronic venous insufficiency [4]. Comorbidities are important in older patients with heart failure (HF) because most of them are associated with worse clinical status and are predictors of poor prognosis [5]. Meanwhile, the drugs for HF or these comorbidities may have an effect on clinical outcomes [6]. Therefore, elderly patients may be more susceptible to CRS.

However, studies focusing on the risk factors of incidence and mortalities in geriatric patients with CRS1 are limited. So the objective of the present study is to identify the risk factors and the prognosis of CRS1 in elderly patients. In the present retrospective study, we aimed to clarify the risk factors and prognosis in elderly patients with CRS1: (1) demographic data; (2) co-morbid condition (classified by Charlson co-morbidity index); (3) laboratory data (including data for renal function, such as estimated glomerular filtration rate, data for nutrition et al.); (4) past history of diseases and use of drugs. Moreover, the prognosis of acute heart failure (AHF) would be studied in this research.

CRS1 is defined as acute CRS, characterized by an acute hear failure (AHF) leading to acute kidney injury (AKI) [1,2,3]. The diagnosis of AHF was based on ESC guidelines for diagnosis and treatment acute and chronic heart failure in 2012. The AHF was described as a period of days or even weeks of deterioration (e.g. increasing breathlessness or oedema), and including others developing HF within hours to minutes (e.g. in association with an acute myocardial infarction). Patients may present with a spectrum of conditions ranging from life-threatening pulmonary oedema or cardiogenic shock to a condition characterized, predominantly, by worsening peripheral oedema [7]. The estimated glomerular filtration rate (eGFR) was calculated use a Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation [8]. Co-morbid condition was classified by Charlson co-morbidity index (CCI) [9].

Use of diuretics was defined those who had been receiving any of the following diuretic therapies with no change in the dose for 3 days. Doses of loop diuretics: three grades of doses of loop diuretics with following cut-offs: low-dose (<40mg/day), medium-dose (40-79 mg/day) and high-dose (≥80mg/day). We assume that 8 mg torasemide is equivalent to approximately 40 mg furosemide. Loop diuretic could be combinated with therapy with a thiazide diuretic or an aldosterone antagonist of any dose [10].

This respective study comprised elderly inpatients with acute heart failure who were aged over 60 years in Guangdong General Hospital, and these patients were in calendar years 2009-2013 with follow-up through October 1, 2013. The study involving human participants was approved by the Ethical Committee of Guangdong General Hospital. Written informed consent was obtained from the patients before the enrollment.

Inclusion criteria: Patients > 60 years old with a diagnosis of AHF met the criteria for inclusion.

Exclusion criteria: (1) patients with stage 5 chronic kidney disease, (2) patients with class IV of CHF New York Heart Association (NYHA), (3) patients with other risk factors except for AHF that may cause AKI, (4) patients deficient of laboratory or clinical data.

Patients were assigned as acute heart failure (AHF) with acute kidney injure (CRS1 group) or without acute kidney injure (NCRS1 group). All data were obtained from electronic records in hospital. All laboratory tests were also performed in clinical laboratory of Guangdong General Hospital.

Data were presented as means ± SDs, medians with interquartile ranges, or proportions as appropriate. Patients were divided into two groups (CRS1 group, NCRS1 group). Continuous variables were compared use the Student t test or Mann-Whitney U test. Categorical variables were compared use the χ² test or Fisher exact test. Variables with P ≤ 0.05 in the univariate analysis were further analyzed by multivariate logistic regression analysis to find the independent factors associated with mortality. All statistical calculations were processed use the SPSS 16.0 software (SPSS Inc., USA). A P value less than 0.05 was considered significant.

Between January 2009 and October 2013, a total of 312 patients with AHF were recruited, and they were all hospitalized in Guangdong General Hospital. The average age was 75.33±9.1, male accounted for 62.82%. The mean eGFR was 57.32ml/ (min.1.73m²), and 24.7% patients were with a history of chronic kidney disease. Of these AHF patients, the incidence of CRS1 accounted for 52.56%, the percentage of patients who underwent dialysis was 11.5%, and the in-hospital mortality rate was 23.2%. Clinical characteristics, including age, sex, CCI, laboratory data, history of disease, clinical outcome are listed in table 1.

Univariate analysis showed that levels of blood urea nitrogen (BUN), Serum creatinine (SCr), eGFR, Brain natriuretic peptide (BNP), serum albumin, hemoglobin, hematocrit, CCI scores, with the history of CKD diseases, New York heart association (NYHA) functional classification, use of diuretics and higher dose of loop diuretic were predictive factors for incidence of CRS1 in the elderly patients during hospitalization (P<0.05). Multivariate analyses showed eGFR<60 ml/ (min.1.73m²) (OR=2.239, P<0.001) and use of diuretics (OR=2.555, P=0.001) were independent risk factors for CRS1 in these AHF patients. On the other while, eGFR (OR=0.968, P=0.025) and serum albumin (OR=0.907, P=0.007) were protective factors for incidence of CRS1 in elderly patients with AHF during hospitalization (Table 2).

Univariate analysis showed that level of serum albumin, with the history of chronic obstructive pulmonary disease, with the history of cerebrovascular disease, use of beta blockers or diuretics, the percentage of dialysis during hospitalization were risk factors for all-cause mortality (P<0.05). Multivariate analysis showed dialysis during hospitalization (OR=10.407, P<0.001) was independent risk factor for in-hospital all-cause mortality in CRS1 patients. Use of beta blockers (OR=0.312, P=0.011) or diuretics (OR=0.345, P=0.040) were protective factors for the elderly patients with CRS1 during hospitalization (Table 3).

We performed univariate and multivariate analyses separately to analyze the risk factors of all-cause mortality of these AHF patients. Univariate results showed that level of BUN, level of SCr, BUN/SCr, eGFR, BNP, serum albumin, hemoglobin, hematocrit, CCI scores, with the history of cerebrovascular diseases, concurrent infection, with history of peripheral vascular diseases, use of beta blocker and received dialysis during hospitalization were predictive factors for overall survival (P<0.05). Multivariate analyses showed higher CCI (CCI score≥3) (OR=4.723, P=0.041), occurrence of AKI (OR=6.096, P=0.008), and dialysis during hospitalization (OR=18.743, P<0.001) were independent risk factors for in-hospital mortality in AHF patients (Table 4).

In this retrospective study, we analyzed the incidence, risk factors and prognosis of cardiorenal syndrome type 1 in elderly patients. We found that incidence of CRS1 was 52.56%. Basic estimated glomerular filtration (eGFR <60 ml/(min. 1.73 m²) and use of diuretics were both associated with the higher risk factors of CRS1 in patients, while higher basic eGFR and serum concentration of albumin were both protective factors for CRS1. There were 23.2% CRS1 patients died during hospitalization. Dialysis was the risk factor for in-hospital mortality in CRS1 patients while use of β-blockers and diuretics displayed as protective factors. The in-hospital mortality of the 312 patients with AHF was 13.1%. CCI score≥3, occurrence of CRS1 and dialysis were risk factors for in hospital mortality in AHF patients.

Several published observational studies showed that the incidences of CRS type 1 were 25.9%-38.9% [11,12,13,14,15]. In our study, incidence of CRS1 in elderly patients was 52.56%. These data indicate that CRS1 may be more prevalent in elderly patients. There may be several explanations for higher incidence of CAS1 in old patient. On one hand, acute heart failure in the elderly is an increasingly common clinical problem associated with high in-hospital and mortality rates worldwide [16]. On the other hand, incidence of AKI in older adults have been increasing due to multiple contributing factors ( such as aggressive surgical and medical treatments), increasing numbers of chronic and comorbid illnesses, greater use of medications and imaging agents, and longer exposures to chronic diseases and nephrotoxins [17]. Therefore, elderly patients with AHF are more susceptible to AKI. These factors may be the reasons for high prevalence of CRS1 in old patients.

Our data showed that the baseline renal function, nutrition station, comorbidities, history of CKD, baseline heart function, use of diuretics and doses of diuretics would contribute to in-hospital CRS1 by univariate analysis. Zehra Eren el al. reported that advanced age, history of hypertension, chronic kidney disease, decreased Hb and eGFR levels were significantly associated with AKI in patients with acute coronary syndrome (ACS) [14]. Valerio Verdiani also showed that older than 75 years, have a history of preexisting chronic renal failure (CRF), higher heart rate (atrial or sinus arrhythmia with a heart rate 100 bpm), higher SCr, and lower eGFR were associated with the development of WRF in AHF patients [18]. Similar to our data, advanced age, baseline renal function, history of CKD and nutrition station were associated with CRS1 by different causes. The difference between these researches and our study were that we focused the risk factors on elderly patients. Moreover, our data showed CCI score≥3, NYHA functional classification, use of diuretic, higher dose of loop diuretic were predictive factors for incidence of CRS1. These three factors were novel and indicated that comorbidities, heart function, drugs might be associated with the incidence of CRS1 in elderly patients.

Multivariate logistic regression analyses showed eGFR<60 ml/ min/1.73m² and use of diuretic were independent risk factors for elderly patients with CRS1. On the other while, higher eGFR and serum albumin were protective factors for this patient group. However, Zehra Eren et al. showed no variable as an independent risk factor for AKI in patients with ACS by multivariate analysis [14]. Similar results including preexisting CRF and age (>75 years) were observed in study reported by Valerio Verdiani et al. We also found that use of diuretics was another independent risk factor of CRS1. This finding may be due to an underlying worsening heart function or to an underuse of medications in these elderly patients. Moreover, this result alerts us that elderly patients were more sensitive to diuretic, and we should pay more attention to the intake and urine volume of old patients with acute heart failure.

In this research, we also analyzed the prognosis of CRS1. There were 23.2% CRS1 patients died during hospitalization, which was higher than several previous studies (from 5.5% to 18.2%) [19]. Doron Aronson et al. reported that age (per 10 years increase), BUN (per 10mg/dl increase) were risk factors of CRS1 [20]. The above results were similar to our research. However, we showed more factors such as nutrition station, comorbidities, diuretic, and dialysis. Multivariate analysis by us showed dialysis during hospitalization was independent risk factors for in-hospital all-cause mortality in elderly patients with CRS1. The explanation for the association between dialysis and the prognosis of CRS1 is that the elderly patients received dialysis were with worse renal function and regulation ability. What's more, our data showed use of beta-blocker and diuretic were protective factors for these patients. Doron Aronson et al also reported that beta-blocker was protective factor in their research, but they did not analyze the role of diuretics in the prognosis of CRS1 patients [20]. Use of diuretics was protective factor of the prognosis of CRS1 in old patients, which seemed to be contradictory to that diuretic was the risk factor to incidence of CRS1. This finding hinted us that properly use of diuretics (not abuse) might protect elderly patients from death.

At last, multivariate analyses in our research showed occurrence of AKI, dialysis during hospitalization and higher CCI scores (≥3) were independent risk factors for in-hospital mortality in AHF patients. Several studies have evaluated the association of the occurrence of AKI in ACS or ADHF patients and mortality rate [21,22,23,24]. They showed that AKI could predict all cause mortality. These results are similar to ours. Moreover, we found dialysis during hospitalization was independent risk factor for in-hospital mortality. Therefore, our research provided more evidence for the prognostic factors for AHF patients and might improve clinical approaches to change outcomes. In our investigation, higher CCI score (≥3) was independent risk factor in old CRS1 patients. This result has not been reported previously. As we know, elderly patients often have more comorbidities. Thus, when making treatment decisions, we should give consideration to the treatment of comorbidities and take systematic strategies to elderly patients with CRS1.

Our study has following limitations. The first one is that this is a retrospective study involving the limitations of the sample size. Guangdong General Hospital is one of hospital with largest cardiovascular centers and geriatric centers in China. Therefore, our data might be expected to reflect the current situation at most large hospitals in China. The second one is the follow-up duration was in hospital and no long follow up. Further prospective studies are needed with large patient groups and long follow up to establish more reliable results.

CRS1 in elderly patients is more prevalent and significantly associated with poor outcome. Reduced basic eGFR, nutrition station and use of diuretic were predictors of occurrence of CRS1, while use of diuretics, use of beta blockers and dialysis were predictors of in-hospital mortality in these patients with CRS1. The evidence above suggests that more suitable treatments for the elderly with CRS1 might be needed.

The authors declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.