Objectives: In this study, our aim was to evaluate the systolic cardiac parameters and related risk factors in children within 6 months after kidney transplant.
Materials and Methods: We retrospectively evaluated 24 children who received kidney transplants. Clinical and laboratory parameters before and after transplant were recorded. Results were evaluated statistically, with a P value less than .05 considered significant.
Results: Before transplant, systolic cardiac functions were within normal limits. After transplant, ejection fraction (63.35% ± 5.38% vs 66.95% ± 4.62%; P = .01) was significantly increased and left ventricular mass index (32.63 ± 17.21 g/m2.7 vs 31.29 ± 15.65 g/m2.7; P = .78) was not significantly decreased, whereas fractional shortening (52.16% ± 15.32% vs 59.8% ± 12.94%; P = .54) did not change. Systolic blood pressure, systolic blood pressure index, diastolic blood pressure, and diastolic blood pressure index values were not statistically different before and after transplant (P > .05). The number of antihypertensive agents was significantly decreased (P = .001). Before and after transplant, cardiac geometry was normal in 15 patients (62.5%) and 17 patients (70.8%).
Conclusions: Our patients, who had stable systolic cardiac function before transplant, showed further improvements in systolic cardiac function even within 6 months after transplant. Therefore, strictly monitored and controlled blood pressure, volume, anemia, and nutrition in children before transplant may play important roles in achieving better cardiac systolic function after kidney transplant.
Key words : Children, Cardiac function, Systolic, Kidney, Transplantation, Short-term
Cardiovascular disease is by far the most important and independent risk factor for morbidity and mortality in every stage of chronic kidney disease, even after kidney transplant.1,2 Loirat and associates3 have reported that cardiovascular disease accounted for 51% of deaths among children on dialysis and 37% in kidney transplant recipients between 1987 and 1990. In a large study from Norway, cardiovascular disease was shown to be the second most common cause of death among children who received kidney transplants.4
Although the risk of death due to cardiovascular disease decreases significantly after kidney transplant, this risk is still 3-fold higher than for the overall pediatric population.5 Left ventricular dysfunction, especially left ventricular hypertrophy (LVH), is the most common pathology in pediatric kidney recipients. Deteriorated graft function, hypertension, hyperlipidemia, obesity, type 2 diabetes mellitus, anemia, and malnutrition are all the determinants of cardiovascular disease in these children.5-9 Although these risk factors are well known in adults, studies that have evaluated systolic cardiac dysfunction and associated risk factors in pediatric kidney recipients are still limited. Therefore, we wanted to assess the systolic functions and related risk factors in children within the first 6 months after kidney transplant.
Materials and Methods
This retrospective study was conducted in 26 children, < 18 years old, who underwent kidney transplant due to end-stage renal disease between 2005 and 2012 at the Izmir Tepecik Training and Research Hospital, Departments of Pediatric Nephrology and Organ Transplantation (Izmir, Turkey). The study, conducted according to the guidelines of the Declaration of Helsinki, was approved by our Institutional Review Board.
Patients with posttransplant creatinine clearance of less than 30 mL/min/1.73m2 were excluded (2 patients). Patient medical records were reviewed for documentation of age, sex, type of dialysis before renal transplant, source of graft, medical history, immunosuppressive regimen, blood pressure index and values, antihypertensive agents, cumulative prednisone dose per kilogram body weight, and presence of graft rejection. Left ventricular functions were evaluated by using echocardiography before and 6 months after renal transplant. Comparisons were made with the latest echocardiography performed before transplant. At the time of echocardiographic evaluation, weight and height also were recorded, and body mass index was calculated. Body height and weight were expressed as (observed height minus median height)/standard deviation (height score) and (observed weight minus median weight)/standard deviation (weight score). Blood pressure was measured in accordance with the recommendations of the “Fourth National Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and Adolescents.”10 Mean systolic and diastolic blood pressure measurements were calculated from the values obtained on the day of evaluation and the 3 previous clinic visits or dialysis sessions (predialysis measurements).
These average values were then divided by the 95th percentile blood pressure measurements for age, sex, and height percentile to produce the blood pressure index. A blood pressure index > 1 was accepted as hypertension. Creatinine clearance was calculated from a timed urine output collection (time, volume, and creatinine concentration) and plasma creatinine using the formula and corrected to a body surface area of 1.73m2. Mean hemoglobin level was calculated as the average hemoglobin level over the 3 months before each echocardiography. Serum albumin, blood lipid, glucose, calcium, phosphorus, parathyroid hormone (PTH), urea, and uric acid levels were evaluated on the day of echocardiography. Urine output before and 6 months after transplant was used as a marker of residual renal function (before) and good graft function (after transplant).
Echocardiographic results were evaluated for all patients at rest and at clinically stable conditions (no edema, minimal interdialytic weight increase in pretransplant) at routine clinic visits with a Philips HD7 XE system by the same cardiologist. During the examination, myocardial and valvar motions were visualized and anatomic substrates of flow abnormalities were evaluated. We measured the systolic functions (ejection fraction and fractional shortening) using 2-dimensional, M-mode, color Doppler echocardiography. Left atrial diameter, interventricular septum, left ventricular posterior wall thicknesses, aortic annulus, and left ventricular end-diastolic volume (LVEDV) diameter also were recorded. Left ventricular mass was calculated using measurements made according to the recommendations of the American Society of Echocardiography: left ventricular mass = 0.8(1.04[(LVEDV diameter + left ventricular posterior wall thicknesses + interventricular septum)3 – (LVEDV diameter)3]) + 0.6 g. Therefore, left ventricular mass index (LVMI) was calculated as left ventricular mass divided by patient’s height (m2.7).11 An LVMI exceeding the 95th percentile for sex and age in normal children and adolescents was used to define LVH.12 Relative wall thickness was calculated by the formula: relative wall thickness = 2 × left ventricular posterior wall thicknesses/LVEDV diameter. A relative wall thickness value ≥ 0.43 was defined as concentric left ventricle geometry.13 Left ventricular dilatation was assessed using the LVEDV diameter index. The LVEDV diameter index was calculated as the ratio of LVEDV diameter measured and the normal LVEDV diameter adjusted to patient body weight in kilograms. An LVEDV diameter index > 1 was accepted as having left ventricular dilatation.
All patients received triple immunosuppressive regimens, including calcineurin inhibitors, mycophenolate mofetil or mycophenolate sodium, and corticosteroids. Induction therapy was selected based on protocol guidelines and transplant risk factors. Patients at high risk for acute rejection (having panel reactive antibodies > 20% or cold ischemia time for > 24 h) received rabbit anti-T-lymphocyte immunoglobulin (ATG Fresenius S 5 mL, TM, Fresenius Corp., Grafelfing, Germany) at 2 to 5 mg/kg daily (for a total 5 doses). Other patients received interleukin 2 receptor antagonist induction with basiliximab (Simulect, Novartis Pharmaceuticals, New York, NY, USA) at 10 mg (weight < 35 kg) or 20 mg (weight > 35 kg) given intraoperatively and on postoperative day 4. Corticosteroids were initiated in the operating room (30 mg/kg/dose) and were tapered to low-dose prednisone (0.1-0.5 mg/kg/d) within 3 months after transplant.
Statistical analyses were performed with SPSS software (SPSS: An IBM Company, version 20.0 for Window, IBM Corporation, Armonk, NY, USA), with results expressed as means ± standard deviation. Paired t tests and chi-square tests were performed to examine differences in categorical variables between groups. Associations were assessed by Pearson product moment correlation and Spearman rank correlation tests to identify the predictors of LVH. A P value of less than .05 was considered statistically significant.
Patient characteristics are shown in Table 1. The mean age at transplant was 11.66 ± 4.09 years. The median duration of dialysis treatment before transplant was 14.11 months. Peritoneal dialysis was the most common form of dialysis modality, performed in 20 patients (83.3%). Only 2 patients (8.3%) had preemptive renal transplant. An equal number of patients received living-donor and deceased-donor renal transplants. During the study period, 5 patients (20.83%) showed biopsy-proven acute allograft rejection. All acute rejections were treated with pulse-steroid therapy and/or plasmapheresis. All patients are still on follow-up in our pediatric transplant unit with good graft function (serum creatinine levels < 2 mg/dL).
Clinical and laboratory parameters
Clinical, biochemical, and medical parameters for all patients are shown in Table 2. Mean body mass index was 16.75 ± 2.09 kg/m2 before transplant and 18.93 ± 2.78 kg/m2 at 6 months after transplant (P = .001). Body mass index, weight, serum and albumin levels all significantly improved after transplant (P < .05). During the posttransplant period, serum creatinine levels (5.47 ± 2.19 mg/dL vs 0.97 ± 0.37 mg/dL), urea levels (111.8 ± 53.15 mg/dL vs 40 ± 23.91 mg/dL), PTH levels (483.91 ± 457.86 U/L vs 98.96 ± 97.06 U/L), creatinine clearance (15.1 ± 9.5 mL/min/1.73m2 vs 86.4 ± 27.3 mL/min/1.73m2), and daily urine volume (787.5 ± 788.1 mL/d vs 2120 ± 743.2 mL/d) also significantly improved (P < .05). Serum uric acid, lipid levels, and calcium-phosphorus product did not change (P > .05). Systolic and diastolic blood pressure measurements were not different between the 2 time periods (P > .05). Although the cumulative dose of steroid intake increased significantly (P = .001), the number of antihypertensive agents used decreased significantly in the early posttransplant period (P = .001).
Echocardiographic values before and after transplant are shown in Table 3. The mean LVMI was not different between the 2 periods (P > .05). The frequency of LVH was 37.5% before transplant and 29.2% at 6 months after transplant (P > .05). Ejection fraction increased significantly from 63.35% ± 5.38% to 66.95% ± 4.62% (P = .01). There were no statistically significant changes in cardiac geometry (P = .17). Before transplant, LVMI was negatively correlated with age at transplant (P = .03; r = -0.46) and patient height (P = .02; r = -0.46), whereas LVEDV diameter (P = .01; r = 0.43) was positively correlated with LVMI. However, 6 months after transplant, LVMI was positively correlated with pretransplant LVMI (P = .02; r = 0.45) (Figure 1) and negatively correlated with posttransplant ejection fraction (P = .01; r = -0.47) and posttransplant fractional shortening (P = .009; r = -0.52). Figure 1 shows the effects of pretransplant LVMI on posttransplant LVMI.
This retrospective study investigated the systolic cardiac function of 24 children who received kidney transplants, examined before transplant, while they were maintained on dialysis or conservative management, and at 6 months after transplant. We demonstrated that preserved systolic cardiac functions shown before transplant were more likely to demonstrate further improvement in systolic cardiac functions even in the early posttransplant period.
It has been reported that cardiac geometry and LVH could be affected by various parameters before and after transplant.1,6,14,15 Successful kidney transplant provides better cardiac performance than dialysis. This can be achieved by the correction of volume status, which has a direct effect on left ventricular structure, and by the normalization of metabolic disturbances, including correction of anemia, improvement in body mass index, achievement of optimal blood pressure control, and reduction of both PTH and calcium-phosphorus product levels.2,16 However, Mitsnefes and associates17 showed that LVH was maintained in children even after kidney transplant. Hernandez and associates18 pointed out that successful kidney transplant did not normalize LVMIs after transplant. They concluded that the persistence of LVH after transplant, manifested as increased LVMI, associated with increased LVMI values and risk factors related to LVH before transplant. On the contrary, our study patients showed an improvement in systolic cardiac functions in the early 6-month posttransplant period (Table 2).
Left ventricular hypertrophy is an important risk factor for the development of cardiovascular morbidity. Hypertension, anemia, malnutrition, obesity, hyperparathyroidism, dyslipidemia, and type 2 diabetes mellitus are important determinants of left ventricular structure.5-9,17 Systolic hypertension is a major determinant of left ventricle geometry, especially concentric changes (remodeling and hypertrophy), after renal transplant.8,17,19-21 In our study group, the indexes of systolic blood pressure before transplant were within normal limits, with parameters showing, although insignificant, a trend toward further improvement during the 6 months after transplant (P = .19). Similarly, the number of antihypertensive agents used was significantly reduced (P = .001), whereas cumulative steroid intake increased (Table 2). However, no significant changes in hypertrophic left ventricle geometry (regarding hypertrophy or remodeling) were observed during this period. Although we did not have a control group, we believe that the improvement in systolic blood pressure indexes could be associated with relatively well preserved cardiac status before kidney transplant. An interesting finding in the present study is the existence of a negative correlation between pretransplant LVMI and patient age at transplant (P = .03; r = -0.46). Although the negative correlation of LVMI with age, particularly in children < 9 years of age, is a reported finding in the normal population, as stated by Khoury and associates,12 we also can speculate that children with end-stage renal disease having a relatively increased LVMI tend to be younger at diagnosis and more likely to have a worse prognosis and more severe complications than children with normal left ventricle geometry after renal transplant.
On the other hand, anemia status, body mass index, lipid levels, calcium-phosphorus product, and PTH levels (significantly) also were improved after transplant. Wilson and associates9 showed a high prevalence of metabolic syndrome among pediatric kidney recipients at the end of the first year after transplant. In our series, only 1 patient developed type 2 diabetes mellitus with no evidence of impaired systolic cardiac function during the 6 months after kidney transplant. Because this study investigated the systolic cardiac functions at 6 months after transplant, we cannot conclude whether metabolic syndrome developed as a consequence of kidney transplant.
One of the major limitations of the present study is its generalizability. This is a retrospective and single-center study with a relatively small sample size and follow-up. In addition, age heterogeneity in the study, with 25% of the study children being less than 10 years old, limits us to calculate and determine the cardiac geometry due to the lack of validated data in children who are less than 10 years old. Therefore, magnetic resonance imaging remains the criterion standard in determining cardiac geometry, which is not used as a regular imaging method in our routine clinical practice.22
In conclusion, patients who have stable systolic cardiac function before transplant show further improvements in systolic cardiac function even within 6 months after transplant. Therefore, despite no control group, strictly monitored and controlled blood pressure, volume, anemia, and nutrition in children before transplant could play important roles in achieving better systolic cardiac function after kidney transplant.
Volume : 15
Issue : 1
Pages : 34 - 39
DOI : 10.6002/ect.2015.0208
From the 1Department of Pediatrics, Izmir Tepecik Training and
Research Hospital, Izmir, Turkey; the 2Department of Pediatric
Nephrology, Izmir Tepecik Training and Research Hospital, Izmir, Turkey; the
3Department of Organ Transplantation, Izmir Tepecik Training and Research
Hospital, Izmir, Turkey; the 4Department of Pediatric Nephrology,
Izmir Katip Celebi University, Izmir, Turkey; and the 5Department of
Pediatric Cardiology, Izmir Tepecik Training and Research Hospital, Izmir,
Acknowledgements: The authors declare that they have no conflicts of interest and received no funding for this study.
Corresponding author: Caner Alparslan, Department of Pediatrics, Izmir Tepecik Training and Research Hospital, Gaziler Cd. No:468 Yeniþehir, Izmir, Turkey
Phone: +90 232 469 6969, +90 533 233 7767 (mobile)
Fax: +90 232 433 0756
Table 1. Patient Characteristics (N = 24)
Table 2. Comparison of Clinical, Biochemical, and Medical Parameters of the Study Group Before and 6 Months After Transplant
Table 3. Comparison of Echocardiographic Parameters Before and 6 Months After Transplant
Figure 1. Effect of Pretransplant Left Ventricular Mass Index on Posttransplant Left Ventricular Mass Index