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Clinical and Translational Research

Incidence and Predictors of Postoperative Atrial Fibrillation in Kidney Transplant Recipients

La Manna, Gaetano1,4; Boriani, Giuseppe2; Capelli, Irene1; Marchetti, Antonio3; Grandinetti, Valeria1; Spazzoli, Alessandra1; Dalmastri, Vittorio1; Todeschini, Paola1; Rucci, Paola3; Stefoni, Sergio1

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doi: 10.1097/TP.0b013e3182a2b492
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Abstract

Postoperative atrial fibrillation (POAF) is a supraventricular arrhythmia that can complicate cardiothoracic and noncardiothoracic surgery. For cardiothoracic surgery, an incidence of 16% to 46% has been reported (1–7). The few studies that evaluated POAF incidence after noncardiothoracic surgery reported an incidence of 0.3% to 0.4% for noncardiothoracic surgery (8, 9) and 8.5% to 10.2% for patients admitted to surgical intensive care units (10, 11). Although often considered a relatively benign arrhythmia, POAF is associated with longer hospitalizations (12), higher in-hospital mortality (13), and complications including thromboembolism and hemodynamic destabilization. Kidney transplant recipients may be more likely to experience POAF because of the frequent presence of risk factors such as hypertension, chronic kidney disease (CKD), and diabetes. Severe hemodynamic instability after kidney transplantation has been associated with an increased risk of delayed graft function (DGF) that influences long-term graft survival (14, 15). Some authors, analyzing U.S. Renal Data System registry data about kidney transplant recipients, reported an incidence of new-onset chronic atrial fibrillation (AF) of 3.6% and 7.3% at 12 and 36 months after kidney transplantation. They also individuate older recipient age, male gender, white race, renal failure from hypertension, and coronary artery disease as risk factors (16).

To our knowledge, no previous study has investigated POAF incidence and predictors in renal transplant recipients. Moreover, there are no scoring criteria available to identify transplant patients at higher risk of experiencing POAF. The CHADS2 and CHA2DS2-VASc scores were designed and are used for thromboembolic risk assessment and to determine the need for long-term antiplatelet or anticoagulant therapy in patients with AF (17–20). These scores include some variables that are considered to be risk factors for AF onset. Therefore, they may be useful to stratify patients for POAF risk and identify those who deserve more attention and resources.

We retrospectively studied kidney and combined kidney/liver transplant recipients to (a) determine POAF incidence and predictors among kidney transplant recipients and (b) examine the CHA2DS2-VASc scores ability to predict POAF in kidney transplant recipients and adapt it to this patient population.

RESULTS

From January 2005 to December 2008, 304 patients (mean±SD age, 51.1±12.5 years) underwent kidney transplant at the Kidney Transplant Centre of St. Orsola University Hospital (Bologna, Italy). Sixteen patients had a history of AF; for three patients, this information was missing. After transplant, 25 (8.2%) patients had at least one AF episode. In 21 patients (6.9% of the total and 84.0% of the AF group), POAF occurred de novo, and in the remaining 4 patients (1.3% of the total and 16% of the AF sample), it was a relapse. Twelve patients with an AF history had no relapse. On average, POAF occurred 4.72±5.75 days after the intervention (median, 3 days). The cumulative POAF risk was highest on the day of surgery (2.5%), increased steeply up to day 3 (5.3%), and reached 9.5% on the 19th day of admission (Fig. 1). The median (range) length of hospital stay in POAF patients 22 (12–69) days, whereas, in patients without POAF, it was 18.5 (12–43) days (P=0.111, Mann–Whitney test). Seventeen (68%) patients had only one POAF episode, 6 (24%) patients experienced two episodes, 1 (4%) patient had three episodes, and 1 (4%) patient had eight episodes. In 7 (28%) patients, the POAF was symptomatic.

FIGURE 1
FIGURE 1:
Risk of POAF in the first 20 days after surgery.

The characteristics of patients who experienced POAF (Group A, n=25) and who did not experience POAF (Group B, n=279) are detailed in Table 1. The mean age of Group A patients was significantly higher (59.7±7.4 vs. 50.3±12.6 years; P<0.001). Patients with a history of AF, diabetes mellitus, myocardial infarction, and vascular disease had a significantly higher risk of developing POAF. Hypertensive nephropathy was unrelated to POAF. Diastolic blood pressure before and after renal transplantation was significantly lower in Group A versus Group B. Moreover, patients undergoing simultaneous liver/kidney transplantation showed an increased risk of developing POAF compared with patients with kidney transplantation alone (P<0.001).

TABLE 1
TABLE 1:
Demographic and clinical characteristics of the study population

Postoperative patient clinical characteristics are presented in Table 2. The postoperative course of POAF patients was characterized by an increased occurrence of DGF and need of dialysis, but these findings were not statistically significant (P=0.570 and 0.065, respectively). None of the posttransplantation complications, such as anemia, hypertension, diabetes, or myocardial infarction, was correlated with an increased POAF risk. Pathologic findings observed during vascular ultrasound examination of the aorta and lower limb vessels performed in the year before kidney transplantation were significantly more common in Group A. Moreover, the left atrium size on echocardiography performed before transplantation was significantly higher in Group A than Group B patients (4.2±0.7 vs. 3.9±0.7 cm, respectively; P<0.050).

TABLE 2
TABLE 2:
Patient characteristics related to transplant

We performed logistic regression analysis using sex, age, body mass index, history of AF, acute myocardial infarction, vascular disease, diabetes, left atrium size, and transplant type as independent variables. Using a backward-stepwise removal of nonsignificant variables, only age, acute myocardial infarction history, and transplant type remained significantly associated with POAF (Table 3). Using receiver operating characteristics (ROC) analysis, we identified a cutoff age of 53 years.

TABLE 3
TABLE 3:
Predictors of POAF in backward-stepwise multiple logistic regression

Using ROC analysis, we also compared the ability of the modified CHA2DS2-VASc with that of the CHA2DS2-VASc score in predicting POAF risk. Figure 2 shows the sensitivity, specificity, and the relative risk of POAF for the different cutoffs of the two scores. The modified CHA2DS2-VASc score had a better predictive validity that the original CHA2DS2-VASc (area under the curve=0.71, 95% confidence interval [CI]=0.63–0.79 vs. area under the curve=0.62, 95% CI=0.52–0.73, respectively; Fig. 2). The cutoff of 3 or more on the modified CHA2DS2-VASc score provided the optimal balance between sensitivity and specificity. Still, at this cutoff, the false-positive rate was high (53%).

FIGURE 2
FIGURE 2:
ROC analysis showing the performance of CHA2DS2-VASc vs. CHA2DS2-VASc_NQ. Sensitivity, specificity, and relative risk of POAF at each cutoff for the CHADS2, CHA2DS2-VASc, and CHA2DS2-VASc_NQ scores.

DISCUSSION

POAF has a considerable incidence after cardiothoracic and noncardiothoracic surgery. In surgical patients, AF may be related to specific factors such as perioperative use of catecholamines, reflex sympathetic activation from volume loss, anemia, pain, fever, and blood glucose abnormalities. There is also evidence that local or systemic inflammation may play a role in POAF; however, its exact mechanisms are not fully understood (21).

Our results indicate an 8.2% incidence of POAF after kidney or combined liver/kidney transplantation. This figure is higher than values reported for other noncardiothoracic surgery in the literature (8, 9), but similar to the POAF incidence in patients admitted to surgical intensive care units, which ranges from 8% to 10% (10, 11). This result suggests the need for closely monitoring kidney recipients after surgery. In our population, POAF occurred on average at day 5. These data are similar to others’ findings (8, 9, 11).

Risk factors for POAF have not been well elucidated and may vary according to the study populations. Age is an important POAF risk factor also in the general population (8). In our study population, age was the strongest POAF risk factor in both univariate and multivariate analyses after adjusting for clinical covariates. Several international guidelines recommended considering age as a risk factor for cardiovascular events in pretransplantation cardiac evaluation (22). We identified a cutoff value of 53 years, which maximizes predictive sensitivity and specificity. This cutoff is below the age of 60 years, which is usually considered in the guidelines as the age at which risk increases. In light of the size of our population, this analysis does not identify a real cutoff threshold for risk of POAF onset, but it has been useful for identifying the opportunity to modify the CHA2DS2-VASc score and how to do it in our population.

We considered also patients with an AF history because this condition is related to a higher POAF risk. In this study, prior AF represented a POAF risk factor only in univariate analysis. Moreover, in our population, a history of myocardial infarction was predictive of POAF onset in kidney transplant recipients in multivariate analysis. This finding is consistent with those of other authors (9, 10) and underscores the importance of cardiac evaluation before kidney transplantation for surgical risk stratification.

In this study, POAF occurred in 6% of patients with kidney transplant surgery and 20% of patients with simultaneous liver/kidney transplantation. A possible explanation is that kidney/liver transplant recipients have more comorbidities and worse clinical conditions compared with kidney-only transplant patients. Fong et al. reported a lower survival rate during the first 3 postoperative months in combined liver/kidney transplant recipients versus kidney-only transplant recipients. In this case, the authors suggested that this result was related to the severity of patients’ pretransplantation medical conditions as shown by the proportion of patients hospitalized in the intensive care unit at the time of transplantation (23).

It is well known that CKD predisposes to an increased AF risk. In fact, several registry studies report that the CKD is associated with an increased risk of AF and related complications (24, 25). CKD patients are frequently affected by diabetes and cardiovascular disease (26, 27). Our univariate analyses indicate that POAF risk increased with the severity of vascular disease, being highest in patients with arterial stenosis. Lower diastolic blood pressure in patients who develop POAF may reflect arterial wall stiffness. We also found an increased POAF risk for patients with a larger left atrium size on echocardiographic examination. Our results emphasize the importance of considering these conditions and the results of instrumental examination in risk assessment for POAF. A correct risk evaluation before surgery may select a high-risk population that requires preventive strategies.

A previous retrospective study carried out on a large patient cohort identified increased age, diabetes, and claudication as predictive for an early posttransplantation cardiovascular event defined as myocardial infarction, undergoing a revascularization procedure, cerebrovascular accident, or death from a cardiovascular cause (28). In a large cohort of kidney transplant recipients, Lentine et al. identified coronary artery disease as risk factor for chronic AF. Our results confirm that these same conditions are predictive for POAF onset after kidney transplant surgery. Lentine et al. (16) reported also other risk factors as predictive of chronic AF after kidney transplantation, such as DGF and posttransplantation diabetes mellitus, which in our population do not reach statistical significance. We do not know whether these differences between the two populations can be traced to their number or to the peculiarities of POAF in which the surgical intervention is a trigger.

To determine the POAF risk in kidney transplant patients, we used the CHA2DS2-VASc score, which is normally used to establish risk for stroke, thromboembolism, and mortality in patients with chronic AF but recently has been proposed for estimating the risk of new-onset AF and hospitalization after AF and atrial flutter (29, 30). The score did not provide for our population a high sensitivity and specificity; in our opinion, it is because kidney transplant patients have a higher POAF risk at ages significantly lower than those considered by the original score. Therefore, we developed an adapted version for kidney transplant patients that consider lower ages. The adapted version performs better than the original CHA2DS2-VASc, but the discriminatory power for clinical applicability was still poor due to a high false-positive error rate.

Stratifying kidney transplant patients for POAF risk is important because they are exposed to hemodynamic instability and may also need hemodialysis after surgery, which can further deteriorate hemodynamic conditions. Moreover, after surgery, these patients may experience sudden electrolyte alterations that may influence cardiac electrophysiology. Lastly, anticoagulant prophylactic strategies recommended for reducing thrombotic risks increase the likelihood of hemorrhagic complications, because drug accumulation is greater in patients with impaired renal function. Therefore, identification of patients who deserve preventive strategies will potentially reduce POAF in kidney transplant recipients.

This study had two important limitations. First, this study was monocentric and included a relatively small sample size. Second, the retrospective design of the study did not allow collection of some important clinical information. For instance, we were unable to evaluate the influence of cardiovascular drugs on POAF in our population.

In conclusion, POAF is a notable complication of kidney transplant surgery. Age, history of myocardial infarction, and simultaneous liver/kidney transplant were the primary risk factors associated with POAF in our population. Our findings suggest that careful clinical evaluation before transplantation is essential for appropriate postoperative patient management.

The modified CHA2DS2-VASc score implementing a lower cutoff for age provides a better discriminatory power in the high-risk population of renal transplant recipients. It may be helpful to stratify POAF risk more precisely and to identify patients who need more thorough cardiologic follow-up and preventive strategies. However, this score needs to be validated prospectively and in larger samples. Prospective studies are needed to test the effectiveness of medical and nonmedical preventive strategies in this population.

MATERIALS AND METHODS

Data Sources and Participant Selection

We retrospectively reviewed clinical charts of adult patients (>18 years old) transplanted between January 2005 and December 2008 at the St. Orsola University Hospital Kidney Transplant Centre (Bologna, Italy). We included single-kidney (from living and deceased donors), double-kidney, and simultaneous liver/kidney transplants. Simultaneous kidney/heart transplants were excluded. The protocol was approved by the Institutional Ethics Committee. We evaluated the POAF incidence in the period between kidney transplant surgery and discharge from the hospital. We examined the day of POAF onset, the number of episodes, and the presence of associated symptoms. Patients were divided into two groups: patients with at least one episode of POAF (Group A) and patients without POAF episodes (Group B).

The clinical and laboratory variables of the two patient groups are reported in Table 1. This table also provides patient histories and recent (within 1 year) cardiovascular examinations performed for patients’ eligibility for kidney transplant (history of diabetes, stroke, or myocardial infarction, arterial stiffness or presence of atherosclerotic plaques in the carotid and femoral arteries, and abdominal aorta by Doppler ultrasound, echocardiography with evaluation of atrial and ventricular dimensions, interventricular septum thickness, ventricular mass, and ejection fraction, and cardiac functional evaluation by stress test or myocardial scintigraphy). For each patient, we calculated the CHADS2 score (cardiac failure, hypertension, age, and diabetes each scored 1 and stroke scored 2) and the CHA2DS2-VASc score (cardiac failure, hypertension, age ≥75 years [scored 2], diabetes, stroke [scored 2], vascular disease, age 65–74 years, female gender, and included arterial stiffness in the vascular disease category). We developed a modified version of the CHA2DS2-VASc scoring system (CHA2DS2-VASc_NQ) by taking into account the different age distribution of transplant candidates and including the following variables: cardiac failure, hypertension, age 61 years or more (scored 2), diabetes, stroke (scored 2), female gender, age 53 to 60 years, and vascular disease. The two age cutoffs of 53 and 61 years used in this modified score were set at the median and the fourth quartile of the age distribution.

Statistical Analyses

Patients with and without POAF were compared on continuous variables using t tests, on ordinal-level variables using Mann–Whitney test, and on categorical variables using chi-square tests or Fisher’s exact test, as appropriate. Variables significantly associated with POAF in univariate analyses were included in a multiple logistic regression analysis. P<0.05 was considered statistically significant. ROC analysis was carried out to determine the predictive validity of the CHADS2, CHA2DS2-VASc, and CHA2DS2-VASc_NQ scores. The POAF risk at admission was estimated using Kaplan–Meier survival analysis. All statistical analyses were carried out using IBM SPSS Statistical Software version 20.0.

ACKNOWLEDGMENTS

The authors thank Helen Spiby for the kind linguistic collaboration related to the research project “Il rigetto a medio e lungo termine nei trapianti d’organo”—Consorzio Interuniversitario Trapianti d’Organo and Dr. Ravaldi Elisa for her data collection activities.

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Keywords:

Postoperative atrial fibrillation; Kidney transplant; CHA2DS2-VASc

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