Heart failure (HF) is a major cardiovascular syndrome associated with a significant risk of mortality and hospitalization.1–3 Congestion and/or hypoperfusion can lead to organ injury, which is associated with increased mortality.4 Renal dysfunction is one of the most frequent noncardiac comorbidities in HF.5 Increased serum creatinine (SCr) levels are very common in acute decompensated HF (ADHF), with an incidence ranging from 20% to 50%.6,7

Several groups have studied the prognostic significance of worsening renal function (WRF) following initiation of diuretic therapy. However, studies have yielded conflicting results.8–11 The timing of creatinine rise may identify different subgroups of patients with different prognoses. The aim of this study was to assess the prognostic impact of the timing of WRF in patients with ADHF.

We studied a single-center retrospective cohort of patients admitted to an HF unit due to ADHF with a ‘warm and wet’ clinical profile (type B) according to the 2016 European Society of Cardiology HF guidelines,1 between January 2014 and August 2018. Patients with chronic kidney disease (CKD) on hemodialysis, need for renal replacement therapy, need for inotropic therapy, no outpatient SCr measurement in the six months before admission, no serial SCr assessment available during hospitalization, or discharge in less than 48 hours were excluded.

During hospitalization patients underwent treatment with intravenous furosemide and started guideline-directed medical therapy as soon as indicated. Data pertaining to the index hospitalization, patient characteristics, laboratory study results and medication use, as well as events during follow-up, were extracted from electronic medical records.

WRF was defined as an increase in SCr of ≥0.3 mg/dl based on the standard definition (from admission to any time during hospitalization).9,10 WRF timing was classified as early, when occurring within 48 hours, or late, when observed after 48 hours of hospitalization (Figure 1). Acute kidney injury (AKI) at admission was defined as a rise in SCr of ≥0.3 mg/dl from outpatient baseline measurement (up to six months before the acute episode as an outpatient) to the first measurement after patient arrival.

Figure 1.

Representation of heart failure patient timeline and the different types of creatinine variation. AKI: acute kidney injury; HF: heart failure; WRF: worsening renal function.

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Patients were then stratified into four groups according to the presence of AKI at admission and the development of early WRF: group 1 (A−/W−) – no AKI at admission and no early WRF; group 2 (A+/W−) – lone AKI (AKI at admission with no early WRF); group 3 (A−/W+) – lone early WRF (no AKI at admission but with early WRF); and group 4 (A+/W+) – AKI at admission and early WRF.

The primary endpoint was a composite of all-cause mortality or hospitalization for cardiovascular events, truncated at one year after admission.

Estimated glomerular filtration rate (eGFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation.12 CKD was defined as eGFR <60 ml/min/1.73 m2.

Categorical variables are presented as frequencies and percentages, and continuous variables as means and standard deviations, or medians and interquartile ranges for variables with skewed distributions. Differences between the experimental groups were assessed by an analysis of variance (ANOVA) model, followed by the Tukey-Kramer test when findings with ANOVA were significant. Kaplan-Meier survival curves were calculated for each patient group. Univariate and multivariate analysis with Cox regression were performed to assess the prognostic value of different parameters. All reported p-values are two-tailed, with a p-value of 0.05 indicating statistical significance. The analysis was performed using IBM SPSS Statistics, version 25 (2017).

The main findings of the current analysis can be summarized as follows: (i) in patients hospitalized for ADHF, standard WRF was associated with all-cause mortality or cardiovascular events at one year; (ii) after adjustment for a set of baseline characteristics and admission laboratory results, the presence of early WRF (either alone or in association with AKI at admission) remained an independent predictor of the primary outcome.

Our findings regarding standard WRF are similar to those previously reported by other studies.8,11,13 In particular, a study by Forman et al. assessing 1004 ADHF patients, the majority of whom had heart failure with reduced ejection fraction (HFrEF), showed an association between WRF and in-hospital death.13 However, other studies showed conflicting results. A prospective study by Metra et al. that included 318 patients revealed that standard WRF was not associated with death or HF hospitalization,9 although a sizable proportion of these patients were treated with dopamine (22%) or inotropes (9%), which may have influenced SCr variation in response to diuretic therapy and renal hemodynamics.9 Similarly, Cowie et al. studied 299 patients with acute decompensated HFrEF and showed no statistically significant association between standard WRF and mortality at six months.10 The majority of these patients developed late WRF (median time to WRF was four days), which, in our study, was not associated with worse outcomes.10 Other studies have been published on WRF, using a wide variety of definitions, hindering the comparability of the results.11,14–16

Another important finding of our work is that early WRF was associated with worse outcomes not only at one year of follow-up, but also at shorter follow-ups, in comparison to late WRF. This underscores the importance of this adverse event in patient hospitalization, which may be explained by the presence of more severe disease, associated with lower cardiac and/or renal reserve, limiting the compensatory response that is usually triggered.

To the best of our knowledge, this is the first study to assess the prognostic impact of WRF timing in patients with ADHF. We aimed to analyze whether early deterioration of renal function, specifically within 48 hours of admission, was a marker of worse prognosis. We employed a 48-hour cut-off for WRF, as this excluded several confounding factors associated with SCr variations during hospitalization. For example, excessive diuretic therapy or initiation/uptitration of renin-angiotensin-aldosterone inhibitors frequently occur during hospitalization and may raise SCr. This type of WRF (often labeled pseudo-WRF) does not seem to be associated with worse outcomes.17 This idea is further corroborated by our study, since we found no association between late WRF (>48 hours after admission) and worse outcomes. Hence, the timing of SCr elevation seems to have an impact in differentiating risk and its pathophysiology.

Furthermore, stratification of patients according to AKI at admission and early WRF status shows that lone early WRF (A−/W+) was associated with a higher risk for the primary outcome. Although this was in a population that was older, had longer hospital stay and had a higher proportion of preserved EF, the prognostic impact remained after controlling for various relevant factors. Conversely, lone AKI at admission (A+/W−) was not an independent predictor of the primary outcome after multivariate Cox regression. These results seem to differ from the work of Shirakabe et al., who concluded that, in a cohort of 1083 ADHF patients, lone WRF (in the first five days) was not associated with higher risk of all-cause death.8 However, as well as using a broader WRF definition, this cohort of patients had more severe disease, and were admitted to an intensive care unit with frequent need for intravenous inotropes/vasopressors, and had a considerably longer hospital stay.8

Each of these subtypes of WRF seems to identify a different set of patients. Changes in renal function in patients with HF are complex and multifactorial. Multiple mechanisms can play a part in WRF, including renal hypoperfusion, activation of the renin-angiotensin-aldosterone and sympathetic systems, and venous congestion.18,19 The clinical importance of each mechanism is likely to vary from patient to patient.8 AKI at admission may also be related to progression of renal disease in the months preceding hospitalization as well as to the cumulative congestion these patients usually develop.4 On the other hand, early WRF may be related to reduced cardiac output and low cardiac and/or low renal reserve, which result in elevation of SCr after initiation of diuretic therapy.4 Consequently, the prognosis varies, depending mostly on the main underlying mechanism of renal dysfunction rather than SCr, which is a limited surrogate biomarker of renal function.

In our opinion, acute renal dysfunction should be differentiated according to various factors. As well as considering absolute variation in SCr, the timing of its appearance should be taken into account. We speculate that early WRF after initiation of diuretic therapy may be a marker of more severe underlying cardiac and/or renal disease, thus identifying patients in whom the usual compensatory mechanisms cannot counteract the hemodynamic effects of diuretics, unveiling reduced organ reserve.

In this study, the presence of WRF, particularly when occurring within 48 hours of initiation of diuretic therapy, was associated with a higher risk of death from any cause or hospitalization for cardiovascular events. The timing of WRF appears to be an important characteristic to take into account when considering the prognostic impact of creatinine variation during hospitalization for ADHF.

Conception and design: JP, GC, BR, IA, CF; data collection: JP, GC, LL, ST, MR, MIS, MM, SM; data analysis: JP, GC, BR; drafting: JP, GC, BR; revising: JP, GC, LL, ST, MR, MIS, MM, SM, BR, CR, IA, CF. All authors read and approved the final manuscript.

The authors have no conflicts of interest to declare.