Abstract
Aims. To assess the impact of microalbuminuria on the development of acute kidney injury and to investigate its prognostic role at long term follow-up in 526 consecutive patients with ST elevation myocardial infarction without previously known diabetes. Methods. Microalbuminuria was measured using immunonephelemetry in the urine collected in the night. Results. Patients with microalbuminuria were older (p = 0.013). They showed higher values of peak glycemia (p = 0.017), peak Tn I (p < 0.001), NT-pro BNP (p = 0.020), ESR (p = 0.003), CRP (p = 0.020), and leukocyte count (p < 0.001). Lower eGFR was observed in patients with microalbuminuria both on admission and during ICCU stay (p = 0.048 and p = 0.003, respectively). A positive correlation was observed between CRP and microalbuminuria (Spearman's rho 0.114, p = 0.024). The composite end point was observed in 73 patients (18 patients died and 59 patients developed acute kidney injury). At multivariable regression analysis, microalbuminuria was an independent predictor of acute kidney injury. At follow-up [42.6 (25th–75th percentile, 17.5–56.8) months], Kaplan–Meier curve analysis showed that patients with microalbuminuria had a lower survival rate in respect to patients without microalbuminuria. Cox regression analysis documented that microalbuminuria was an independent predictor of long term mortality (HR: 1.089; 97% CI 1.036–1.145; p < 0.001). Conclusions. In a large series of STEMI patients without previously known diabetes submitted to PCI, microalbuminuria, as a marker of endothelial permeability following higher systemic inflammatory activation and larger infarct lesions, is an independent predictor for the development acute kidney injury. Furthermore, microalbuminuria identifies a subset of patients at higher risk for long term mortality.
Introduction
Microalbuminuria is a known marker of vascular permeability and endothelial dysfunction and has been found to be predictive of outcome in a wide variety of chronic and acute conditions, such as neoplastic disease (Citation1), surgery (Citation2), acute pancreatitis (Citation3), and trauma (Citation4). In acute settings, microalbuminuria has been shown to be a useful tool to predict outcome in critically ill adult patients admitted to an intensive care unit (Citation5–7). In a large cohort of acute cardiac patients, we (Citation8) observed that microalbuminuria represents an independent predictor for early mortality, being strictly linked to the inflammatory activation and to acute glucose values, as part of the response to stress.
Moreover, microalbuminuria is able to predict illness severity and the development of complications, such as sepsis, acute respiratory failure and multiorgan failure, in medical, surgical, and trauma patients (Citation5–7,Citation9). Its presence has been recognized as a useful predictor for the renal complications in burn patients (Citation10) and in patients without diabetes and with primary hypertension (Citation11).
In patients with acute myocardial infarction data on the prognostic significance of microalbuminuria are so far controversial and no information is available on the relation between microalbuminuria and the development of in-hospital acute kidney injury in these patients.
The present investigation was aimed at assessing the impact of microalbuminuria on the development of acute kidney injury in 526 consecutive patients with ST-elevation myocardial infarction (STEMI) without previously known diabetes submitted to mechanical revascularization. We furthermore investigated the prognostic role of microalbuminuria at long term follow-up.
Methods
From 1st January 2004 to 31st December 2009, 526 consecutive patients with STEMI (within 12 hours from symptoms’ onset) and without a previous history of diabetes were admitted to our ICCU, which is located at a tertiary center. In our hospital, in Florence, the reperfusion strategy of STEMI patients is represented by primary PCI (Citation12–14). Exclusion criteria were as follows: pre-existing chronic renal failure (defined at history), no urine output on the first day of admission, on renal replacement therapy, or overtly bloody urine (Citation8).
The diagnosis of STEMI was based on the criteria of the American College of Cardiology/American Heart Association (Citation15).
Ventilatory support (mechanical and/or non- invasive ventilation) and/or renal replacement therapy (continuous venous–venous hemodiaultrafiltration – CVVHDF) were used when needed (Citation12,Citation14).
Microalbuminuria was measured using immunonephelemetry and defined as an albumin excretion rate (20–200 µg/min) in the urine collected in the night (Citation16). Patients with macroalbuminuria were not included. On ICCU admission, after PCI, in a fasting blood sample the following parameters were measured: glucose (mmol/l), insulin (mUI/l), troponin I (Tn I, ng/ml), uric acid (µm/l) (Citation17), NT-pro brain natriuretic peptide (NT-BNP) (pg/ml) (Citation12), leukocytes count (*103/µl), fibrinogen (mg/dl), C-reactive protein (CRP, mg/dl), and erythrocyte sedimentation rate (ESR). Admission creatinine was measured in order to calculate admission glomerular filtration rate (ml/min/1.73 m2) (MDRD formula: values are expressed quantitatively; age, sex p-creatine and weight are taken into account). Creatinine was measured once a day throughout ICCU stay and nadir eGFR was also considered. Glucose values and Tn I were measured three times a day and peak glucose and peak Tn I were considered, respectively. Acute insulin resistance was defined according to the homeostatic model assessment index, as previously described. Subjects whose values exceeded the sex-specific 75th percentile (i.e., 1.80 for women and 2.12 for men) were considered to have insulin resistance (HOMA-IR) (Citation13,Citation18).
Transthoracic two-dimensional echo-cardiography was performed in order to measure left ventricular ejection fraction (LVEF) on admission and at discharge.
Acute kidney injury was defined as an absolute increase in serum creatinine level of 26 µmol/l or more, or a relative increase in serum creatinine level of 50% or more (Citation19,Citation20).
The development of acute kidney injury during ICCU-stay and in-hospital death was the composite primary end-point.
The study protocol was in accordance with the Declaration of Helsinki and approved by the local Ethics Committee. Informed consent was obtained in all patients before enrollment.
Statistical analysis
Analysis has been performed using SPSS 13.0 statistical package (SPSS Inc., Chicago, IL, USA). Categorical data are expressed as frequencies and percentages; continuous data are reported as mean ± SD or median (25th–75th percentile), according to a normal or not normal distribution, as assessed by one-sample Kolmogorov–Smirnov test. Data have been analyzed by means of χ2 (or Fisher's exact test when expected counts in almost one cell was less than 5) for categorical data and Student's t-test or Mann–Whitney U test for continuous data, according to the shape of their distribution. Correlation between microalbuminuria and C-reactive protein was investigated with Spearman's rho. Multivariable logistic regression analysis was performed in order to identify predictor(s) of the composite end-point (in-hospital mortality or acute kidney injury); Hosmer–Lemeshow goodness-of-fit test and Nagelkerke R2 have been reported. We used Kaplan–Meier survival analysis to assess differences, if any, for death at follow-up between patients whose microalbuminuria was < 20 or ≥ 20 µg/min; log-rank test has been reported. Risk proportionality has been assessed by means of a graphic model, plotting partial residuals against time (follow-up length) in order to take into account both the pattern of their distribution (visually) and the significance of the respective slopes. Neither evidence of a pattern nor slopes significantly different from zero were found in any of the predictors used in our model. After assessment of risk proportionality, a multivariable Cox regression analysis has been conducted in order to identify predictors of long-term death. In both multivariable analyses, variables for inclusion were carefully chosen, between those considered clinically relevant or those which showed a univariate relationship with ICCU death, given the number of events available, to ensure parsimony of the final model. In all cases a p value < 0.05 was considered statistically significant.
Results
shows the clinical characteristics of patients enrolled in the study. Anterior myocardial infarction was the most frequent location. In-hospital mortality rate was 3.4%.
Table I. Clinical and angiographic characteristics of patients with ST elevation myocardial infarction included in the study.
As depicted in , patients with microalbuminuria were older (p = 0.013). They showed higher values of peak glycemia (p = 0.017), peak Tn I (p < 0.001), NT-pro BNP (p = 0.020), ESR (p = 0.003), CRP (p = 0.020), and leukocyte count (p < 0.001). Lower eGFR was observed in patients with microalbuminuria both on admission and during ICCU stay (p = 0.048 and p = 0.003, respectively). In-hospital mortality did not differ between the two subgroups. Ventilatory support and dopamine were more frequently used in patients with microalbuminuria ().
Table II. Comparison between patients with and without microalbuminuria.
Table III. Use of device and inotropic agents.
A positive correlation was observed between CRP and microalbuminuria (Spearman's rho 0.114, p = 0.024).
At multivariable regression analysis the variables independently associated with the composite end-point (in-hospital death and acute kidney injury) are depicted in . Seventy-three patients exhibited the composite end-point, while 59 patients showed acute kidney injury. Microalbuminuria was not related to ICCU death at univariate analysis (OR 1.008, 95% CI 0.999–1.018, p = 0.098) and at multivariable regression analysis (). Microalbuminuria was an independent predictor only for acute kidney injury.
Table IV. Multivariable regression analysis.
At follow-up [42.6 (25th–75th percentile, 17.5–56.8) months], Kaplan–Meier curve analysis (which comprises all patients, also those with reduced eGFR) showed that patients with microalbuminuria had a lower survival rate in respect to patients without microalbuminuria (). At Cox analysis, the following variables were independently associated with long-term mortality: age (1 year step; HR: 1.079; 97% CI 1.047–1.112; p < 0.001; Wald: 24.556), discharge LVEF (1% step; HR: 0.941; 97% CI 0.913–0.969; p < 0.001; Wald: 16.435), admission eGFR (1 ml/min/1.73 m2 step; HR: 0.985; 97% CI 0.973–0.998; p = 0.026; Wald: 4.970), microalbuminuria (10 µg/min step; HR: 1.089; 97% CI 1.036–1.145; p < 0.001; Wald: 11.134).
Figure 1. Kaplan–Meier survival curves.
Discussion
The main finding of the present investigation, performed in consecutive STEMI patients without a previous history of diabetes submitted to primary PCI, is that microalbuminuria, measured on ICCU admission, is independently associated with the development of acute kidney injury. At long term, microalbuminuria is independently associated with lower survival rate.
In critically ill patients admitted to a General Intensive Care Unit, a relationship was described between microalbuminuria levels (or its increase) and the duration of the vasopressor therapy (Citation6), the development of respiratory failure (Citation6,Citation9), and the duration of mechanical ventilation (Citation21).
In the present investigation, performed in a large series of non-diabetic STEMI patients, we observed, for the first time, that the presence of microalbuminuria is associated with a more significant decline in renal function (as indicated by nadir eGFR, and therefore it may be a marker of kidney disease) and it is independently associated with the development of acute kidney injury. This phenomenon can be related to the higher inflammatory activation shown by patients with microalbuminuria (as indicated by ESR and leukocyte count) and to the higher infarct size (as inferred by peak Tn I). According to our data, it can be hypothesized that a higher systemic inflammatory response following larger infarct size may lead to the occurrence of microalbuminuria which, as the expression of increased endothelial permeability within the renal vasculature becomes a predictor for the development of acute kidney injury. The correlation between microalbuminuria and C-reactive protein observed in our series supports this contention.
Data on the impact of microalbuminuria on early death in patients with acute myocardial infarction are controversial and discrepancies may be related to population selection criteria (diabetic vs. non- diabetic) and the type of revascularization (thrombolysis vs. mechanical revascularization, which is known to influence early mortality (Citation13)). Some studies, mainly performed in the thrombolytic era, documented that in patients with acute myocardial infarction (Citation22–23) microalbuminuria yielded prognostic information about in-hospital mortality. In particular, Berton et al. (Citation23) enrolled 475 patients with acute myocardial infarction (among whom diabetic patients were 24%); in this series revascularization was performed only in the 37% by thrombolysis and early mortality was 11%. Similarly, in the paper by Berton et al. (Citation22), the in-hospital mortality rate was 7.7% and only a small percentage of patients were submitted to thrombolysis.
On the other hand, we recently (Citation24) observed in 242 hypertensive STEMI patients without previously known diabetes and submitted to primary PCI that microalbuminuria, though a common finding, was not associated with in-hospital death. In the present investigation, performed in a larger series of STEMI patients we confirm that microalbuminuria is not associated with an increased risk of early mortality. This can probably be related to the fact that in-hospital mortality was significantly lower in our series in respect to that reported in previous papers including STEMI patients mainly submitted to thrombolysis [ranging from 4.5% (35) to 7.11% (34) and 7.2% (32)].
Furthermore, we observed for the first time in STEMI patients submitted to mechanical revascularization that microalbuminuria is a predictor for long term mortality. Factors accounting for this phenomenon can only be hypothesized in our series. Microalbuminuria may be viewed as a marker of endothelial dysfunction (thus being associated with enhanced atherosclerosis) (Citation6,Citation9) and, concomitantly as an index of a higher systemic activation, following larger infarct lesions. Finally, the long term prognostic role of microalbuminuria may be indirectly referable to its relation with C-reactive protein, a well-known strong independent predictor for mortality in patients with acute myocardial infarction. However, our findings are in agreement with previous studies (Citation25) performed in the thrombolytic era and reporting an association between microalbuminuria and long term poorer survival. Moreover, Chen et al. (Citation26) observed in 246 STEMI patients submitted to mechanical revascularization that admission microalbuminuria levels are associated with impaired myocardial flow and a higher 6-month mortality rate. In the series by Chen et al. (Citation26), diabetic patients were also included.
A possible limitation of the present study is represented by the fact that microalbuminuria was measured only once, on ICCU admission. However, the aim of the present investigation was to assess the ability of microalbuminuria in improving early risk assessment in STEMI patients submitted to mechanical revascularization. The possibility that patients with preexisting microalbuminuria (unknown on ICCU admission) have been included in the study cannot be ruled out. However, taken into account the large number of patients included in the present investigation, and the fact that microalbuminuria was associated with higher values of peak Tn I (which is strictly related to the acute ischemic event), it can be strongly supposed that the number of patients with preexisting microalbuminuria may be quite small.
In conclusions, according to our data, in a large series of STEMI patients without previously known diabetes submitted to mechanical revascularization, microalbuminuria, as a marker of endothelial permeability following higher systemic inflammatory activation and larger infarct lesions, is an independent predictor for the development acute kidney injury. Furthermore, microalbuminuria identifies a subset of patients at higher risk for long term mortality.
Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper. The study protocol was approved by the local Ethics Committee.
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