Echocardiographic changes and risk factors for left ventricular hypertrophy in children and adolescents after renal transplantation

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1 Pediatr Transplantation 2004: 8: Printed in UK. All rights reserved Copyright Ó 2004 Blackwell Munksgaard Pediatric Transplantation Echocardiographic changes and risk factors for left ventricular hypertrophy in children and adolescents after renal transplantation El-Husseini AA, Sheashaa HA, Hassan NA, El-Demerdash FM, Sobh MA, Ghoneim MA. Echocardiographic changes and risk factors for left ventricular hypertrophy in children and adolescents after renal transplantation. Pediatr Transplantation 2004: 8: Ó 2004 Blackwell Munksgaard Abstract: Long-term consequences of cardiac alteration in children with chronic renal failure and after renal transplantation are largely unknown. In chronic uremia, cardiomyopathy manifests itself as systolic dysfunction, concentric left ventricular hypertrophy (LVH) or left ventricular dilatation. The correction of uremic state by renal transplantation leads to normalization of left ventricular contractility, regression of LVH and improvement of cavity volume and so dialysis patients with uremic cardiomyopathy would benefit from renal transplantation. We studied 73 patients, aged 17 yr or less, who underwent renal transplantation in our center. This cross-sectional study was performed 4.6 yr (median) after transplantation. Of the total, 48 were males and 25 were females. Transthoracic echocardiographic examination was performed for all cases. The effects of clinical, demographic, biochemical and therapeutic data on echocardiographic parameters were assessed. Multivariate analysis was used to assess the relation between the risk factors and the left ventricular muscle mass index. The most common echocardiographic abnormalities were the LVH (47.9%), left atrial enlargement (31.5%) and left ventricular dilatation and systolic dysfunction (13.7% for each). The pretransplant dialysis, arteriovenous fistula, acute rejection, cumulative steroid dose per square meter surface area, post-transplant hypertension, anemia and graft dysfunction were significant risk factors for LVH by univariate analysis. The significant factors by multivariate analysis were pretransplant dialysis, post-transplant hypertension and anemia. From this study we may conclude that LVH is a common problem among renal transplant children and adolescents. Early transplantation, control of hypertension and correction of anemia may be beneficial regarding left ventricular function and structure. Amr A. El-Husseini, Hussein A. Sheashaa, Nabil A. Hassan, Fawzia M. El-Demerdash, Mohamed A. Sobh and Mohamed A. Ghoneim Mansoura Urology and Nephrology Center, Mansoura University, Mansoura, Egypt Key words: echocardiography left ventricular muscle mass index left ventricular function left ventricular hypertrophy renal transplantation children Dr Amr El-Husseini, MD, Assistant Lecturer of Nephrology, Urology and Nephrology Center, Mansoura University, Egypt Tel.: amr_2000_2002@yahoo.com Accepted for publication 3 December 2003 Abbreviations: ACE, angiotensin-converting enzyme; AOD, aortic diameter; CI, confidence interval; CRF, chronic renal failure; EDTA, European Dialysis and Transplant Association; EDV, end-diastole volume; EF, ejection fraction; ESRD, end-stage renal disease; ESV, end-systole volume; FS, fractional shortening; LAD, left atrial diameter; IV- STD, inter-ventricular septal thickness at end diastole; IV- STS, inter-ventricular septal thickness at systole; LVEDD, left ventricular end-diastolic diameter; LVESD, left-ventricular end-systolic diameter; LVH, left ventricular hypertrophy; LVM, left ventricular mass; LVMI, left ventricular mass index; LVPWD, left ventricular posterior wall thickness at end diastole; SV, stroke volume. Cardiac abnormalities are observed in most children and adolescents with ESRD after renal transplantation. These are important causes of morbidity and mortality in this population. In pediatric patients who died in Europe on renal replacement therapy between 1987 and 1990, a cardiovascular cause of death was noted in 51% of dialyzed and 37% of transplanted subjects (1). Cardiac alterations appear to be less prevalent in pediatric than in adult patients with CRF, but no recent comprehensive study on their frequency has been published in the pediatric 249

2 El-Husseini et al. age group. In adult patients the myocardial lesions induced by CRF are often accompanied by cardiovascular risk factors such as atherosclerosis, essential hypertension, diabetes, myocardial infarction or endocarditis, which are rarely observed in the young. As these factors become more and more relevant with advancing age, early recognition of cardiac abnormalities and preventive measures are imperative in children with CRF and after transplantation (2). The development of heart failure and uremic cardiomyopathy is partially explained by hypertension, diabetes mellitus, anemia, hypoalbuminemia or hyperparathyroidism. Unrecognized volume overload and the arteriovenous access may also contribute to left ventricular dilatation. Inadequate dialysis may predispose to cardiomyopathy, particularly as uremia per se has an adverse impact on cardiac myocytes (3). Renal transplantation will correct uremia, anemia, hypoalbuminemia, hyperparathyroidism and volume overload, but other risk factors may persist, such as high blood pressure, ischemic heart disease, hyperlipidemia, functioning arteriovenous access and diabetes mellitus (4). After renal transplantation, left ventricular contractility improves in selected patients with systolic dysfunctions, even in those with severe symptomatic disease. Some investigators have demonstrated improvement in LVM and volume following transplantation (5, 6), while others have not (7, 8). We therefore studied 73 patients who underwent renal transplantation at the age of 17 yr or less in our center. Transthoracic echocardiography was performed for all cases. The aims of the study were to assess the echocardiographic changes and to determine the risk factors for LVH among our children and adolescent renal transplant patients. Patients and methods This cross-sectional study was started in Mansoura Urology and Nephrology Center in Patients were eligible for entry to the study if they had received renal allotransplants from 6 months. Patient data Medical history and examination findings prior to transplantation were collected from patientsõ files. Follow-up data on patient and graft survival were obtained from clinical records. Pretransplant data Recipient age, sex, original kidney disease, blood group, blood transfusion, pretransplant medical problems such as hypertension and pretransplant renal replacement therapy were recorded. Follow-up data Regimen of immunosuppressive medications, acute rejection episodes, chronic rejection, total dose of steroids, and presence of functioning arteriovenous fistula, post-transplant hypertension and graft function were assessed. Hypertensive resting pressure was considered above 95th centile according to age and sex (9). Patients transplanted before 1989 were treated conventionally with a maintenance immunosuppressive regimen comprising daily oral prednisolone between 7.5 and 10 mg and azathioprine 2 mg/kg. A triple regimen with prednisolone, cyclosporine A and azathioprine has been introduced since Cyclosporine A was administered so that wholeblood trough levels were maintained between 100 and 150 ng/ml. Tacrolimus was introduced as a primary therapy since 1998, but it was introduced as a secondary immunosuppression since Cardiovascular medications registered were loop-diuretics, thiazides, calcium-channel antagonist, ACE inhibitors, beta and alpha adrenergic receptor blockers. Fifty percent of our hypertensives patients received beta blockers. Calcium channel blockers, alpha blockers and diuretics were received by 35, 19and 12% of patients, respectively. Echocardiographic examination M-mode, two-dimensional and Doppler echocardiographic examination was performed for 73 pediatric renal transplants using Toshiba SSA 380 A (Power vision). This machine used sector scanner MHz. Subjects were studied in the left lateral decubitus with the transducer in the third or fourth left intercostal space. A longaxis parasternal view was visualized. The M-mode cursor was placed just below the tips of the mitral value (at the level of the chordae tendinae), as perpendicular as possible to the interventricular septum and the left ventricular posterior wall. Measurements taken The following measurements were taken: LVEDD, LVESD, IVSTD, IVSTS, LVPWD, LAD and AOD. Parameters calculated from the M-mode measurements The following parameters were calculated from the M-mode measurements: Left ventricular volumes at EDV and ESV were estimated according to the method of Tortoledo et al. (10), EF ¼ (EDV ESV)/EDV, FS ¼ (EDD ESD)/EDD, SV ¼ EDV ESV, LVM in grams was determined from Devereux and Reichek s formula (11), LVM ¼ 1.04 [(LVEDD + IVST + LVPWD) 3 LVEDD 3 ] LVMI in g/m 2 ¼ LVM/body surface area. The accepted upper limit of normal LVMI values are g/m 2 for males and g/m 2 for females (12). Normal values for EF are 55 70% and for FS% are 30 40% (13). Diameters, thickness and volume are corrected for body surface area and normal ranges are considered according to Feigenbaum appendix (14). Pulsed wave Doppler examination of mitral valve was conducted to determine the blood velocity of early diastolic filling phase (E) and atrial filling phase (A). Normally the ratio E/A is >1. Diastolic dysfunction was suggested when the ratio is 1 (15). 250

3 Echocardiographic changes and risk factors Statistical analysis Results were presented as means with standard deviation for nominally distributed data, or medians with percentiles for non-nominal distributions. Nominally distributed continuous variables were compared using t-test. Categorical variables were compared using chi-square tests. All statistical tests were two-sided, with a p-value of <0.05 taken to indicate statistical significance. Independent variables used in the multivariate analysis were pretransplant dialysis, arteriovenous fistula, acute rejection, cumulative steroid dose per square meter surface area, post-transplant hypertension, anemia and graft dysfunction. The spss statistics package (spss V11.0, SPSS Inc., USA) was used for these analyses (16). Results Our study included 73 renal transplant patients who underwent renal transplantation at the age of 17 yr or less. All patients received live donor transplant, 45 were males while 25 were females. At the time of the study the mean age of our cases was 16.3 ± 3.2 yr, the mean serum creatinine was 1.9± 3.1 mg/dl, the mean corrected creatinine clearance was 62 ± 25.9mL/min/ 1.73 m 2. Eighteen patients received preemptive transplantation while six received peritoneal dialysis and 49received hemodialysis. The median dialysis duration was 8 months (range 0 60 months). The median duration of renal disease before transplantation was 10 months (range 6 66 months). Thirty seven patients were hypertensive before renal transplantation, 15 of them were normalized after transplantation while 22 showed persistent hypertension. Thirty eight patients were hypertensive after transplantation 16 of them were de novo. More than half of our cases received nonspecific blood transfusion with a median number of 3 units transfusion. Transthoracic echocardiographic examination was performed for all patients at different time points after transplantation (range months), with a median period of 4.6 yr. Table 1. Echocardiographic abnormalities among our patients Abnormality Number (out of 73) Percentage Pericardial effusion Mitral regurgitation Mitral stenosis Aortic regurgitation Left atrial enlargement Left ventricular dilatation Left ventricular hypertrophy Reduced FS Reduced EF Left ventricular diastolic dysfunction The most common echocardiographic abnormalities were the LVH (47.9%), left atrial enlargement (31.5%) and left ventricular dilatation and systolic dysfunction (13.7% for each). Four patients had valvular diseases (one had mitral stenosis, one had aortic regurgitation and Table 2. Effects of pretransplant variables on LVMI of 73 pediatric transplants Number (out of 73) Abnormal LVMI p-value Age (yr) (50.00%) (41.93%) (53.13%) Sex Male (48.89%) Female (46.43%) Original kidney disease Hypoplastic kidney 19 8 (42.10%) Glomerular disease 18 8 (44.44%) Tubulointerstitial disease (55.56%) Hereditary nephritis 9 4 (44.44%) Unknown 9 5 (55.56%) Pretransplant dialysis Preemptive 18 4 (22.22%) Peritoneal dialysis 6 2 (33.33%) Hemodialysis (59.18%) Pretransplant blood transfusion No (41.67%) Yes (54.41%) Pretransplant hypertension No (44.44%) Yes (51.35%) Table 3. Effects of post-transplant variables on LVMI of 73 pediatric transplants Number Abnormal LVMI p-value Immunosuppressive regimen Cyclosporine based (53.57%) Tacrolimus based 16 5 (31.25%) Acute rejection episode No (38.30%) Yes (65.38%) Chronic rejection No (45.90%) Yes 12 7 (58.33%) Alternate-day steroid No (46.30%) Yes (52.63%) Cumulative steroid dose 16 g or less (42.50%) More than 16 g (54.55%) Cumulative steroid index 10 g or less (39.02%) More than 10 g (59.94%) Arteriovenous fistula No (38.30%) Yes (65.38%) Post-transplant hypertension No (37.14%) Yes (57.89%)

4 El-Husseini et al. Table 4. Effect of post-transplant laboratory parameters on LVMI of 73 pediatric transplants Normal LVMI (n ¼ 38) Abnormal LVMI (n ¼ 35) p-value Serum creatinine (mg/dl) Creatinine clearance (ml/min) Hemoglobin (g/dl) Serum cholesterol (mg/dl) Values given for LVMI are mean s.d. Table 5. The significant risk factors for LVH by multivariate analysis (logistic regression model) Variable Regression estimate (B) two patients had mitral regurgitation) and one patient had mild pericardial effusion (Table 1). Among all of the pretransplant variables only hemodialysis was the significant variable for the abnormal LVMI (Table 2). Among all of the post-transplant variables, acute rejection episodes, cumulative steroid dose per square meter surface area, presence of functioning arteriovenous fistula and patients with post-transplant hypertension had significantly abnormal LVMI (Table 3). The graft dysfunction (as assessed by the serum creatinine and creatinine clearance) and a lower hemoglobin level were significant risk factors for abnormal LVMI (Table 4). Using logistic regression analysis, the significant risk factors for LVH were pretransplant dialysis, post-transplant hypertension and anemia (Table 5). Discussion Cardiac disease has extensively been investigated in adult patients, but to a much lesser extent in children and adolescents with CRF and after renal transplantation. LVH is a strong and independent predictor of death and cardiac failure (2). Concentric LVH usually results from LV pressure overload and is the most frequent manifestation of uremic cardiomyopathy in s.e. Relative risk Exp (B) (95% CI) p-value Pretransplant dialysis Preemptive Peritoneal dialysis (1.2, 5.4) Hemodialysis (6.3, 78.3) <0.001 Hypertension No Yes Anemia No (Hb 12 g/dl) Yes (Hb < 12 g/dl) chronic uremia, being present in 42% of patients on starting ESRD therapy (17). The degree of LVH is associated with hypertension and anemia (18). Correction of uremia by renal transplantation was associated with 17% improvement in LVMI, similar to the degree of regression of hypertrophy observed on partial correction of anemia with erythropoietin. The degree of regression of LVH may have been limited by hypertension, as a significant association was observed between fall in blood pressure and fall in LVMI. They reported that the degree of improvement in LV contractility after transplantation was 56% increase in fractional shortening and it was larger than that expected for correction of anemia (19). Reduction of the LVMI after renal transplantation has not been a universal observation, more recent studies did not find significant change in LVMI following transplantation (20), also Mitsnefes et al. (8) showed that there was no significant difference in the mean values for the LVMI in children and adolescents while on dialysis and after renal transplantation. Transthoracic echocardiographic examination was performed for 73 of our pediatric renal transplants; they were 45 males and 28 females. Echocardiographic study was performed at different time points after transplantation (range months), with a mean period of 4.6 ± 3.1 yr after transplantation. The most common echocardiographic abnormality was the LVH (47.9%). This prevalence was higher in comparison to other studies as in the only large study performed by EDTA in children which reported incidence of 22% of post-transplant LVH (21). But recent reports indicate a high prevalence of LVH in children on dialysis and after renal transplantation, Mitsnefes et al. (8) found that the prevalence of LVH was 56% among children and adolescents after renal transplantation. On the other hand, Johnstone and his colleagues reported that LVH was more frequent and more severe in children after transplantation compared with those on hemodialysis or in preterminal renal failure. This report also discussed the methodological difficulties of obtaining a meaningful expression of LVM in this age group (22). Left atrial enlargement was a common abnormality among our cases (31.5%) and this was also reported by others (6). Rysz et al. (23) concluded that abnormal function of left atrium in the course of uremia is not fully corrected after renal transplantation despite elimination of many cardiovascular complications observed in chronic renal disease. 252

5 Echocardiographic changes and risk factors Systolic dysfunction was also a prevalent abnormality in our series (13.7%). Harnett and his colleagues found that systolic dysfunction is present in 16% of patients on the initiation of ESRD therapy and they reported that it is a significant predictor of the development of cardiac failure and of mortality (18). In our patients the prevalence of LV dilatation and systolic dysfunction (as evidenced by reduced FS% and EF) were 13.7% and this was comparable to Parfrey et al. (19) who reported an incidence of 12% after renal transplantation. The effect of pretransplant dialysis on the left ventricular function and structure had been documented previously as many risk factors associate dialysis as hypertension, hypervolemia, anemia, arteriovenous fistula, pericarditis, endocarditis, stimulation of the rennin angiotensin system, sympathetic over-activity, hyperparathyroidism, metabolic acidosis, uremic toxins, acute phase reactant, B2 microglobulin, and hyperhomocysteinemia. The development of LVH during dialysis may persist after transplantation (2). Alvares et al. (24) found an increased LVMI in children with prior hemodialysis before renal transplantation, especially if dialysis lasted for more than 2 yr and they concluded that although cardiac hypertrophy and dilatation is reversible after renal transplantation, it would seem that children may benefit from an earlier transplantation. After transplantation, LVH is mainly dependant on the presence of hypertension. A significant association was observed between fall in blood pressure and fall in LVMI (25). Also Mitsnefs et al. (8) found by multivariate analysis that hypertension was independent predictor for increased LVMI after renal transplantation in children and adolescents and they concluded that control of blood pressure might be an important factor in regression or prevention of progression of LVH in these patients. Also anemia was reported as independent predictor for LVH (19). Alvares and his colleagues reported that correction of hematocrit correlated with reduction of LVMI after renal transplantation in children (24). Morris et al. (26) followed-up six children for 12 months after successful renal transplantation; the children showed persistent anemia despite dramatic improvement in biochemistry and they found no significant change in cardiovascular function. They concluded that anemia is the more dominant influence on cardiovascular function in endstage renal failure (26). In conclusion LVH is a common problem among children and adolescents after renal transplantation. Early transplantation, control of hypertension and correction of anemia may be beneficial regarding left ventricular function and structure. References 1. Ehrich JHH, Loirat C, Brunner FP. Report of management of renal failure in children in Europe. XXII. Nephrol Dial Transplant 1992: 7: Scharer K, Schmidt KG, Soergel M. Cardiac function and structure in patients with chronic renal failure. Pediatr Nephrol 1999: 13: Weisenee D, Low-Friedrich I, Richle M, Bereiter-Hahn J, Schoeppe W. In vitro approach to Ôuremic cardiomyopathyõ. Nephron 1993: 65: Kasiske BL. Risk factors for accelerated atherosclerosis in renal transplant recipients. Am J Med 1988: 84: Himelman R, Landzberg J, Simoson J. Cardiac consequences of renal transplantation: changes in left ventricular morphology and function. J Am Coll Cardiol 1988: 12: Sahagun G, Espinola N, Lafragua M, et al. 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