EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Objectives: Cardiovascular disease is the most-common cause of mortality in patients with end-stage renal disease and renal transplant. Prolongation of QTc_max and QTc dispersion are risk factors of cardiac arrhythmias and mortality. This study compares the changes of QT parameters before hemodialysis, after hemodialysis, and after renal transplant.

Materials and Methods: Patient candidates for renal transplant were selected. Mean serum electrolyte and 12-lead electrocardiogram were recorded (1) immediately, (2) before and, (3) after the last dialysis session before renal transplant, (4) and 2 weeks after a kidney transplant in 34 patients with normal graft function (plasma Cr ≤ 176.8 µmol/L). Each QT interval was corrected for the patient’s heart rate using Bazett’s formula. The QT parameters (QTd, QTcd, QTc_max) were compared between prehemodialysis, posthemodialysis, and 2 weeks after renal transplant using a paired t test and a general liner model repeated measure. The correlation between QT parameter changes and serum electrolyte and acid-base alternation was analyzed.

Results: The corrected maximal QT interval (QTc_max) decreased significantly after successful renal transplant compared to prehemodialysis (P = .002) and posthemodialysis (P = .003) with a paired t test and a General Liner Model Repeated Measure (P < .001) between the 3 groups. Also, the mean of QTc_max decreased significantly after renal transplant (P = .001) compared to what it was before hemodialysis and after hemodialysis. There was a significant correlation (r= -0.37) between reduction of QTc_max and serum Ca level (P = .01) in postrenal transplant period.

Conclusions: Renal transplant with normal graft function decrease QTc_max compared to prehemodialysis and posthemodialysis that may correlate with normalization of electrolytes from the uremic state of the normal kidney function.

Key words : QT interval, Renal transplant, Hemodialysis, Cardiovascular disease, Repolarization

Kidney transplant is the treatment of choice for end-stage renal disease that restores the patients' quality of life and reduces morbidity and mortality rates caused by renal failure and its complications.¹ However, transplant recipients die prematurely and increasingly because of cardiovascular disease.^{2, 3} A cardiovascular event in a transplant recipient may be the result of a pretransplant disease process, a direct effect of immunosuppressant medications, or the result of exposure to a several traditional and nontraditional risk factors.⁴

As posttransplant longevity has increased, nonimmune complications related to the transplant and posttransplant course have emerged as important factors in defining long-term outcomes.⁵ Although increased awareness of cardiovascular disease has resulted in a reduction in cardiovascular disease-related deaths over time, cardiovascular disease remains the major known cause of death in transplant recipients, and is a significant barrier to improving long-term outcomes in kidney transplant.^{6, 7} The risk of ventricular arrhythmias is known to increase during hemodialysis (HD) treatment, but the cause of this phenomenon remains unidentified. Clinical and experimental data have shown that increased QT dispersion (QTd) is associated with severe ventricular arrhythmias and sudden cardiac death.^8-10 QT dispersion (QTc_max - QT_min) reflects heterogeneity of cardiac repolarization, and increased dispersion is known to predispose the heart to ventricular arrhythmias and sudden cardiac death.¹¹ Thus, screening of cardiac disease is recommended to prevent cardiovascular death after renal transplant.¹² Chronic renal failure patients on maintenance HD have several electrocardiogram (ECG) abnormalities and cardiac arrhythmias.

A reliable noninvasive predictive test of sudden death is therefore important. The interlead variation in duration of the QT interval on the surface ECG corrected with heart rate (QTc dispersion) might serve as a surrogate for ventricular arrhythmia. Prolonged QTc dispersion is commonly encountered in dialysis patients and possesses an increased risk of cardiovascular mortality. QT dispersion might be affected by shifts of the intracellular electrolytes during dialysis and increasing deposition of iron in the cardiac muscles in these patients with underlying heart diseases. Increased QTd is associated with various cardiac diseases and predicts sudden death. Chronic renal failure patients, and patients on hemodialysis, have been shown to have an increased QTd, which may rise significantly after hemodialysis, and evidence of increased QTd in renal transplant patients is rare.^13-14 Although no well-designed study has been done, the factors contributing to prolongation of QTc dispersion should be avoided.^{15, 16} This study compared the changes of QT parameters in end-stage renal disease (ESRD) patients before and after hemodialysis and after successful renal transplant, with a correlation between these changes and serum electrolytes levels.

Materials and Methods

Patients who underwent kidney transplant in transplant ward of Razi hospital were selected. There were 34 patients (16 men, 18 women; mean age, 39.11 ± 13.32 y; range, 16-66 y) enrolled in the study after exclusion for congestive heart failure, coronary artery disease, or consumption of class 1 or 3 antiarrhythmic drugs. All patients or their guardians were given written informed consent before entering the study. All protocols were approved by the ethics committee of the institution before the study began, and they conformed to the ethical guidelines of the 1975 Helsinki Declaration.

Conventional 12-lead ECG was recorded to assess QT dispersion, 10 minutes before and after the last hemodialysis session, and 2 weeks after a successful renal transplant (plasma Cr ≤ 176.8 µmol/L). Simultaneous 12-lead ECG was recorded by means of an ECG recorder at a paper speed of 25 mm/s. On every occasion, the ECG was obtained after a 5-minute rest, with the patients lying in the supine position. Three consecutive cardiac cycles were measured and averaged. The QT intervals for each lead were measured manually with calipers by 1 observer. The QT interval was measured from the first deflection of the electrocardiogram complex to the point of the T-wave offset, defined by a return of the terminal T wave to the isoelectric TP baseline. In the presence of U wave interrupting the T wave, the terminal portion of the visible T wave was extrapolated to the TP baseline to define the point of the T-wave offset. If the end of T wave could not be reliably determined, the lead was not included in the analysis. Each QT interval was corrected for the patient’s heart rate using Bazett’s formula: QTc = QT/ √RR (ms), where QTc is the corrected QT interval. QT and QTc dispersions were defined as differences between the minimal and maximal QT and QTc values in each of the 12 leads studied.

To determine the intraobserver variability of QT interval and QT interval dispersion measurement, all ECG strips were evaluated by 1 investigator on 2 different occasions. Data are expressed as means ± SD. The differences of QT parameters between pre-HD and post-HD, pre-HD and posttransplant, post-HD and posttransplant were compared using the paired t test, the General Linear Model Repeated Measure, and posthoc Bonferroni test.

Plasma levels of electrolytes (sodium, potassium, magnesium, calcium, and phosphorous), blood urea nitrogen, serum creatinine, and arterial blood gas were tested in patients immediately before and after the last dialysis session and also, 2 weeks after kidney transplant. Calcium and magnesium levels were corrected based on serum albumin levels.

Results of quantitative variables are reported as means ± standard deviation. Statistical analyses were performed by the General Linear Model for Repeat Measure (for comparison of the QT parameters) and pairwise comparisons were performed using the t test for independent variables.

The correlation between QT parameters changes and serum electrolyte and acid-base alterations were studied with the Pearson product moment correlation analysis. Values for P < .05 were considered significant. Statistical analyses were performed with SPSS software (SPSS: An IBM Company, version 18.0, IBM Corporation, Armonk, New York, USA).

Baseline characteristics are shown in Table 1. Glomerulonephritis (35%) was the most-common cause of ESRD in these patients, followed by hypertension (28%), diabetes mellitus (15%), unknown (15%), and autosomal dominant polycystic kidney disease (ADPKD) (7%). Our results represent as the mean values with SD and the median and the 25th percentile (P-25), the 75th percentile (P-75) of the maximal QTc interval, and the QT dispersion and QTc dispersion in pre-HD, post-HD, and post-RT period (Table 2).

There were no significant differences in the average results of QT dispersion and QTc dispersion between the 3 groups using the General Linear Model Repeated Measure (Table 3).

Whereas the maximum QTc was significantly lower in post-RT (0.449 ± 0.027) compared to pre-HD (0.471 ± 0.43) with P = .003, and post-HD (0.473 ± 0.04) with P = .002 (Table 3).

Also, alteration of QTc_max between pre-HD and post-HD was nonsignificant (P = .779). Comparison with General Liner Model repeated measure between 3 groups demonstrates that the mean of serum BUN (P = .0001), creatinine (P = .0001), potassium (P = .0001), magnesium (P = .006), and phosphate (P < .0001) decreased significantly, and the mean of serum PH increase significantly (P < .0001).

No significant differences were observed in the levels of calcium between pre-HD, post-HD, and post-RT periods (Table 4).

There was a significant correlation (r= -0.37) between a reduction of QTc_max and serum Ca level (P = .01) in post-RT (Figure 1); although there were no significant correlative changes between other QT parameters, serum electrolytes, and PH.

The QT interval reflects the duration of ventricular myocardial repolarization and depolarization, and is highly dependent on heart rate. The QT interval is shorter at a faster heart rate, and longer at a slower heart rate. A prolonged QT interval has been found to be associated with electrical instability of the myocardium and leads to adverse cardiovascular outcomes, including ventricular fibrillation and sudden death.^{17, 18} Preclinical evaluation of delayed ventricular repolarization, manifested as a prolonged QT interval, reflects the electrical instability of the myocardium. It is routinely used as an indicator of potential risk of proarrhythmia, such as impending torsades de pointes, ventricular fibrillation, and sudden death.^{19, 20} The cardiovascular complication rate is increased in high-risk patients with prolonged QT intervals.¹⁷ QTd, as a noninvasive method, is a marker of myocardial electrical instability and a predictor of arrhythmic events. It seems to reflect the autonomic regulation of cardiovascular function, with increased QTd reflecting higher sympathetic and lower parasympathetic inputs to the heart.²¹

Cardiovascular mortality and morbidity are common in patients with chronic kidney disease and in those with hemodialysis. This is often caused by the higher incidence of events, such as arrhythmias, secondary to prolonged QT and QTc dispersion intervals.^{16, 22-23}

Arrhythmias are frequently observed in ESRD patients receiving hemodialysis and may be because of the high rate of sudden deaths.^{10, 16, 24-25} On the other hand, QT dispersion has become useful for predicting and evaluating ventricular arrhythmias.²⁶ Patients with long QT intervals have more frequent ventricular premature beats and sudden death than those with normal QT intervals.²³ Although chronic renal failure patients and patients on hemodialysis have been shown to have an increased QTd, evidence of increased QTd in renal transplant patients is rare.¹³

In this study, we showed that the QTc_max was a marker of risk for arrhythmias and sudden death but were reduced with successful renal transplant compared to pre-HD (P = .002) and post-HD (P = .003).

Studies have shown that renal transplant recipients had similar QTd and QTcd compared with control subjects, and repolarization abnormalities in prerenal transplant patients improved significantly after transplant.^{13, 27} Normalization of the QTd after renal transplant may be because of the correction of several factors responsible for increased QTd in uremic patients.^{13, 16}

In our study, using the General Linear Model Repeated Measure, the mean of serum K (P = .0001), Mg (P = .006), and P (P < .0001) decreased significantly. Mean PH increased significantly (P < .0001). And the mean serum Ca⁺⁺and Na⁺ did not change significantly in post-RT compared with pre-HD and post-HD periods.

Plasma Na, K, and ionized Ca levels, appear to be the main determinants of QTc duration in HD patients. Changes in plasma Na, K, and ionized Ca in HD have significant effects on QTcd.²⁸ Electrocardiogram data demonstrate that the risk of arrhythmia could be higher with decreased plasma Na, K, and decreased ionized Ca during HD.²⁹

A study showed that hemodialysis increases the QTc interval in ESRD patients, mainly because of rapid changes in plasma electrolyte concentrations^{16, 30}; another study indicated that there was no correlation between the changes in QTd and the changes in serum cations. However, the change in QTc correlated inversely with the change in serum calcium level.³¹ Another study showed that QTc_max and QTd increased in HD patients, and started to decrease during the first month after transplant; the percentage of change in QTd during the third month was significantly correlated with the percentage of change of serum calcium.³²

In the present study, there was a significant correlation between the reduction of QTc_max with a serum Ca level (r=-0.37) (P = .01) in postrenal transplant patients. The underlying mechanism is unclear, but the effects of calcium concentration on the acid-base status and K level also may be potentially effective.

The reasons for improved survival with renal transplant compared with dialysis are unclear. A possible mechanism is that the recovery of renal function with a functional renal allograft lowers the inflammatory and or oxidative state found in patients undergoing chronic dialysis. This has been reported in some studies for levels of C-reactive protein, TNF-alpha, and interlukin-6.³³

Another contributing factor may be a lessening of left ventricular hypertrophy after transplant. Such improvement may decrease the risk of mortality from coronary heart disease.^34-35

With successful renal transplant, maximal QTc decreases toward normal compared with patients on hemodialysis. This correction may be because of the effects of normalization of electrolyte and acid-base changes, lessening of left ventricular hypertrophy, and inflammation in kidney transplant recipients.

Volume: 10 Issue: 2 April 2012

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