- Email: [email protected]
Effect of Immunosuppressive Therapy on Cardiovascular Risk Factor Prevalence in Kidney-Transplanted Children: Comparative Study
Effect of Immunosuppressive Therapy on Cardiovascular Risk Factor Prevalence in Kidney-Transplanted Children: Comparative Study J.A. García-Belloa,*, E.G. Romo-Del Ríoa, E. Mendoza-Gómezb, P.A. Camarena-Ariasb, and M. Santos-Caballerob a Departments of Pediatric Nephrology and bTransplants, UMAE Hospital General Centro Médico La Raza, Instituto Mexicano del Seguro Social, México City, Mexico
ABSTRACT Background. Cardiovascular disease (CVD) is the second major cause of death in kidney-transplanted children. Cardiovascular risk factors (CVRF) prevalence after transplant may increase. The effect of immunosuppressive therapy has not been fully studied in children. The objective of the study was to measure and compare CVRF prevalence in kidney-transplanted children, depending of immunosuppressive therapy. Methods. The study was an observational, transversal, retrospective, comparative study of pediatric patients transplanted at UMAE Hospital General Centro Medico La Raza. All patients were treated with prednisone and mycophenolic acid and any of cyclosporine, tacrolimus, or sirolimus. Demographic, clinical, and biochemical variables and immunosuppressive therapy were evaluated. We used analysis of variance, c2, and Fisher tests with the SPSS 18.0 statistical program. Results. One hundred fifteen patients were studied. Sixty-five (56.5%) were male, and median age was 18.5 2.3 years. Seventy-eight (67.2%) were transplanted from a living related donor. Prevalence of anemia and nephrotic proteinuria was significantly less in patients treated with tacrolimus. Those treated with cyclosporine had a significantly greater prevalence of increased LDL-cholesterol, increased serum phosphorus, and increased calcium-phosphorus. Those treated with tacrolimus had lower, not significant, prevalence of hypertension, hyperuricemia, hypoalbuminemia, hypercholesterolemia, hypertriglyceridemia, and low serum HDL-cholesterol than those treated with sirolimus and cyclosporine. In multivariate analysis, patients treated with cyclosporine had significantly more probability of increased phosphorus (OR, 10.65; 95% CI, 2.75e41.16, P ¼ .001) and calcium-phosphorus (OR, 37.94; 95% CI, 3.45e416.17, P ¼ .003) than those treated with tacrolimus. Conclusions. Patients treated with tacrolimus had less prevalence of CVRF than those treated with cyclosporine or sirolimus. Tacrolimus is the best immunosuppressive option to diminish CVRF in children after kidney transplantation.
C
HRONIC RENAL DISEASE (CKD) is a public health problem around the world, and its incidence and prevalence is increasing, as well as the costs. K/DOQI guidelines define CKD as “renal damage for 3 or more months defined by structural or functional abnormalities with or without decrease in glomerular filtration rate (GFR) manifested by histopathological abnormalities or with presence of renal damage markers including abnormalities in blood or urine composition, or image tests; or as GFR <60 mL/min/1.73 m2 body surface (BS) for 3 or more months with or without renal damage” [1]. ª 2016 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
Transplantation Proceedings, 48, 639e642 (2016)
In the United States, children 0 to 19 years old account for 1% of patients treated with dialysis, according to data from United States Renal Disease Statistics (USRDS). In 2007, 1245 children, 14.5 per million of habitants, began
*Address correspondence to Juan Antonio García-Bello, Department of Pediatric Nephrology, UMAE Hospital General Centro Médico La Raza, Instituto Mexicano del Seguro Social, México City, Mexico. E-mail: [email protected] 0041-1345/16 http://dx.doi.org/10.1016/j.transproceed.2016.02.034
639
640
GARCÍA-BELLO, ROMO-DEL RÍO, MENDOZA-GÓMEZ ET AL Table 1. Biochemical Characteristics of Kidney-Transplanted Patients, Depending on Immunosuppression Therapy Used
Variable
Total n ¼ 115 Value (SD)
Hemoglobin, g/dL Uric acid, mg/dL Albumin, g/dL Total cholesterol, mg/dL Triglycerides, mg/dL HDL-cholesterol, mg/dL LDL-cholesterol, mg/dL Calcium, mg/dL Phosphorus, mg/dL Calcium phosphorus Proteinuria, mg/m2/h‡ Cr Cl, mL/min/1.73 m2 SC
13.71 2.41 6.12 1.61 4.62 0.41 167.77 38.75 141.33 66.63 49.37 17.74 132.27 37.75 9.62 0.74 2.70e6.80 (1.27) 40.99 (9.89) 5.60 (6.00) 83.99 43.21
Tacrolimus n ¼ 78 Value (SD)
13.96 5.87 4.70 161.43 138.50 52.24 122.36 9.67 4.13 40.03 4.83 87.12
Sirolimus n ¼ 18 Value (SD)
(2.34) (1.65) (0.41)* (33.51) (66.37) (15.44) (35.54)* (0.80) (0.82)* (8.82)* (4.67)† (42.39)
13.14 6.76 4.35 184.05 162.94 38.50 137.82 9.44 3.95 36.61 19.58 65.19
(2.55) (1.34) (0.33)* (45.59) (75.56) (32.66) (31.81) (0.39) (1.03)† (9.49)† (21.65)† (28.71)
Cyclosporine n ¼ 19 Value (SD)
13.21 6.53 4.59 174.10 132.78 45.92 169.01 9.62 5.09 49.04 6.62 92.80
(2.51) (1.54) (0.32) (44.48) (59.61) (19.48) (28.81)* (0.73) (1.02)*,† (10.49)*,† (6.7)† (51.83)
P Value
.265 .051 .004 .051 .315 .606 <.001 .505 <.001 <.001 .001 .097
Values are presented as means and standard deviations or medians with interquartile intervals. *,†P values <.05 between groups (post hoc Bonferroni test). ‡ ANOVA or Kruskal-Wallis tests were used.
substitutive treatment for CKD, and 7209 children, 84.6 per million of habitants, were receiving such treatment (USRD, 2011). In Mexico in 2008, there were more than 120,000 patients with terminal CKD; 15,000 were children [2]. Cardiovascular disease (CVD) is major cause of death in patients with CKD. In pediatric patients in 2002, USRDS data show that CVD was the death cause in 8549 pediatric patients on chronic dialysis, accounting for 27% of death causes. In transplanted patients, CVD was the death cause in 22% patients in 2011 [3]. Traditional cardiovascular risk factors (CVRF) have been identified in adults such as age, male sex, hypertension, diabetes, lipid disturbances, and physical inactivity. CVRF related to CKD are added: anemia, hypervolemia, and hyperparathyroidism. CVRF related to treatment modality increases morbidity and mortality, such as glucose overload in peritoneal dialysis patients [4]. Children usually have no diabetes, smoking, or age effects and therefore they deserve separate studies. Although renal transplantation (RT) is the treatment of choice for CKD patients, it does not lower CVD prevalence or prevalence of CVRF. In children, it appears that CVRF increases after successful RT [5]. Between multiple causes of CVD in renal-transplanted children, most of immunosuppressive drugs used have secondary effects on cardiovascular risk. Calcineurin inhibitors such as cyclosporine and tacrolimus cause hypertension. mTOR inhibitors induce dyslipidemia. Corticosteroids and tacrolimus predispose to insulin resistance and affect insulin synthesis, which can generate development of diabetes [6]. To date, we do not know the impact of the kind of immunosuppression on prevalence of cardiovascular risk factors in the pediatric patients transplanted at our hospital. The objective of the study was to measure and compare the prevalence of cardiovascular risk factors in kidney-transplanted children according to received immunosuppression.
METHODS The study was an observational, transversal, retrolective, comparative study of children 6 to 21 years old transplanted before the age of 16 years in Hospital General Centro Medico La Raza. We evaluated sex, age, CKD etiology, nutritional status considering malnourished to patients in whom height zeta score was under 2, and overweight or obesity to patients who satisfied criteria of International Obesity Task Force (IOFT) according their body mass index for age and sex [7]. Patients were considered as hypertensive when systolic or diastolic pressure was greater than 95 percentile for sex, age, and height percentile according to validated values of the American Heart Association [8,9]. After patient fasting, we measured hemoglobin, calcium, phosphorus, albumin, total cholesterol, triglycerides, HDLcholesterol, LDL-cholesterol, and uric acid by use of the colorimetric method in the automatized method with Modular PP (Roche Diagnostics, Japan). Low albumin was considered when <4 g/dL. According to the National Cholesterol Educational Program [10], triglyceride levels were considered elevated when 110 mg/dL, low HDL-cholesterol when <40 mg/dL, and elevated LDL-cholesterol when 110 mg/dL. Elevated uric acid was considered when it was superior to normal level for age. Corrected calcium was calculated as Ca (mg/dL) þ 0.8 (4 albumin in mg/dL) and compared with K/DOQI guidelines. Phosphorus was defined as low, normal, or elevated according to validated tables [11]. The calciumphosphorus index was stratified according to K/DOQI guidelines: for children age >13 years as abnormal when >55 or normal when &55, and for children 6 to 12 years old, abnormal when >65 and normal when &65. Creatinine clearance was measured and stratified according to K/DOQI guidelines. Proteinuria was considered when >4 mg/m2/h and nephrotic proteinuria when >40 mg/m2/h. Means with standard deviations, medians with interquartile intervals, frequencies, and proportions for descriptive statistics were calculated. The c2, Fisher test, and analysis of variance (ANOVA) were used to determine if association existed for variables with immunosuppressive therapy. The SPSS 18.0 statistic program was used, and P values <.05 were considered significant.
RESULTS
One hundred fifteen patients were studied. Sixty-five (56.5%) were male, with mean age 18.5 2.3 years. Time
IMMUNOSUPPRESSIVE THERAPY IN KIDNEY-TRANSPLANTED CHILDREN
641
Table 2. Cardiovascular Risk Factor Prevalence in Kidney-Transplanted Patients, Depending on Immunosuppression Therapy Used Risk Factor
Desnutrition Overweight/obesity Hypertension Anemia Hyperuricemia Hypoalbuminemia Hypercholesterolemia Hypertriglyceridemia Low HDL-cholesterol Increased LDL-cholesterol Proteinuria Nephrotic proteinuria Decreased CrCl Hypercalcemia Hypocalcemia Hyperphosphatemia Increased Ca P
Total n ¼ 115
60 14 16 27 27 7 20 70 4 82 64 9 86 52 8 32 10
(52.1) (12.1) (13.9) (23.4) (23.4) (6.0) (17.3) (60.8) (3.4) (71.3) (55.6) (7.8) (74.7) (45.2) (6.9) (27.8) (8.6)
Tacrolimus n ¼ 78
40 9 7 13 16 3 10 45 1 49 41 3 57 40 7 15 3
Sirolimus n ¼ 18
(51.3%) (11.5%) (9.0%) (16.7%) (20.5%) (3.8%) (12.8%) (57.7%) (11.1%) (62.8%) (52.6%) (3.8%) (73.1%) (51.3%) (9.0%) (19.2%) (3.8%)
from transplant was 50.73 34.95 months. Table 1 shows variable values in all patients and according to immunosuppression received. Table 2 shows the prevalence of cardiovascular risk factors in all patients and according to immunosuppression received. Anemia prevalence and nephrotic proteinuria were significantly less in tacrolimus-treated patients. Those treated with cyclosporine had significantly higher prevalence of increased LDL-cholesterol, increased phosphorus, and increased calcium-phosphorus product. Those treated with tacrolimus had less, but not statistically significant, prevalence of hypertension, increased uric acid, low serum albumin, increased total cholesterol, increased triglycerides, and low HDL-cholesterol, than those treated with sirolimus and cyclosporine. In multivariate analysis adjusted for sex, age, nutritional status, proteinuria, and CKD stage, patients treated with cyclosporine showed significantly more probability of increased phosphorus (OR, 10.65; 95% CI, 2.75e41.16; P ¼ .001) and calcium-phosphorus (OR, 37.9; 95% CI; 3.45e416.17, P ¼ .003) than those treated with tacrolimus. No other significant association was found (Table 3).
8 5 5 8 6 2 6 13 1 14 12 4 13 5 0 4 1
(44.4%) (27.8%) (27.8%) (44.4%) (33.3%) (11.1%) (33.3%) (72.2%) (50.0%) (77.8%) (66.7%) (22.2%) (72.2%) (27.8%) (0.0%) (22.2%) (5.6%)
Cyclosporine n ¼ 19
12 0 4 6 5 2 4 12 2 19 11 2 16 7 1 13 6
(63.2%) (0.0%) (21.1%) (31.6%) (26.3%) (10.5%) (21.1%) (63.2%) (40.0%) (100%) (57.9%) (10.5%) (74.8%) (36.8%) (5.3%) (68.4%) (31.6%)
P Value
.138 .071 .029 .487 .344 .106 .510 .334 .005 .022 .447 .106 .001 .001
DISCUSSION
The prevalence of cardiovascular risk factors was not different from that reported by other authors. In our study, there was no significant difference in prevalence of hypertension according to immunosuppression used, but, in those treated with sirolimus and cyclosporine, the prevalence of hypertension was over the mean of all patients. The mechanism for cyclosporine-induced hypertension is not fully understood, but many have been implicated. Gordjani et al [12] showed a significant association between cyclosporine trough levels and hypertension. Calcineurin inhibitors can induce hypertension by afferent arteriolar vasoconstriction, sodium and water retention, sympathetic overactivity, renin system stimulation, and impaired nitric oxideedependent vasodilatation. Anti-mTOR agents produce dyslipidemia in a dosedependent way that may contribute to development of cardiovascular disease after transplantation [13]. Nevertheless, in the atheromatosis animal model, sirolimus administration was able to reduce 50% of aortic atheromatous lesions. That was accompanied by less expression of interleukins (IL) implicated in the atheromatous process (IL-10) versus the control group
Table 3. Multivariate Analysis (Logistic Regression) Immunosuppressive
Tacrolimus Sirolimus
Cyclosporine
Risk Factor
OR
95% CI
P Value
Increased LDL-cholesterol Hyperphosphatemia Increased Ca P Hypoalbuminemia Increased LDL-cholesterol Hyperphosphatemia Increased Ca P Hypoalbuminemia
1.00 3.45 1.25 4.27 1.90 1.86 10.65 37.94 2.39
0.66e18.07 0.26e6.05 0.19e96.50 0.21e17.04 0.001e109.54 2.75e41.16 3.45e416.17 0.29e19.25
.141 .777 .361 .564 .998 .001 .003 .413
Variables included age, sex, nutritional status, proteinuria, CKD stage.
642
[14]. Although in previous studies there were no differences in serum lipid levels between belatacept and cyclosporine, more patients in the cyclosporine group required treatment with lipid-lowering medications [15]. Anti-mTOR agents can generate proteinuria, particularly in patients with previous renal damage [16]. This proteinuria is a predictor of endothelial dysfunction and mortality in transplanted patients [17]. We found no previous studies reporting calcium phosphorus to be different among patients treated with specific immunosuppressive agents. In summary, in our study, patients treated with tacrolimus had a minor prevalence of most cardiovascular risk factors compared with those treated with cyclosporine or sirolimus. Significant association of immunosuppressive agent was found only with anemia, serum albumin, proteinuria, and increased LDL-cholesterol, phosphorus, and calciumphosphorus product. In multivariate analysis, patients treated with sirolimus showed significantly more probability of increased phosphorus and calcium-phosphorus than those treated with cyclosporine. Tacrolimus was the better option for immunosuppression to decrease cardiovascular risk in studied patients. In pediatric transplanted patients, in which cardiovascular disease is still the second cause of death, to avoid drug-induced risk is primordial, and to choose the best immunosuppression is primordial.
REFERENCES [1] National Kidney Foundation. NKF/DOQI Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation, Classification and Stratification. Am J Kidney Dis 2002;39(Suppl 1):S1e266. [2] General Direction of Information in Health. Mexico City: Health Department & National Institute of Statistics and Geography; 2008. [3] US Renal Data System: USRDS 2011 Annual Data Report: Atlas of Chronic Kidney Disease and End-Stage Renal Disease in the United States. Bethesda, Maryland: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 2011.
GARCÍA-BELLO, ROMO-DEL RÍO, MENDOZA-GÓMEZ ET AL [4] Goicoechea M, de Vinuesa SG, Gómez-Campderá F, Luño J. Predictive cardiovascular risk factors in patients with chronic kidney disease. Kidney Int 2005;67(Suppl 93):S35e8. [5] Mitsnefes MM. Cardiovascular disease in children with chronic kidney disease. J Am Soc Nephrol 2012;23:578e85. [6] Marques Vidas M, Lopez Lafuente J. Cardiovascular disease in kidney transplantation. Clinical Hospital, San Carlos, Madrid, and University Hospital, Alcorcon, Madrid. 2008;15:149e58. [7] Cole E, Levey A, Kurian SM, et al. Chronic kidney disease as a global health problem in public medical care: approach and initiative-proposals of Kidney Disease Improving Global Outcomes. Kidney Int 2007;3:232e45. [8] National High Blood Pressure Education Program Working Group on Hypertension Control in Children and Adolescents. Update on the 1987 Task Force on High Blood Pressure in children and adolescents: a working group report from the National High Blood Pressure Education Program. Pediatrics 1996;98:649e58. [9] Falkner B, Daniels SR. Summary of the Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and Adolescents. Hypertension 2004;44:387e8. [10] National Cholesterol Education Program (NCEP): highlights of the report of the Expert Panel on Blood Cholesterol Levels in Children and Adolescents. Pediatrics 1992;89:495e501. [11] Gunn IR. Biological variation of serum and urine creatinine and creatinine clearance. Ann Clin Biochem 1999;26:302e3. [12] Gordjani N, Offner G, Hoyer PF, Brodehl J. Hypertension after renal transplantation in patients treated with cyclosporine and azathioprine. Arch Dis Child 1990;65:275e9. [13] Groth CG, Bäckman L, Morales JM, et al. Sirolimus (rapamycin)-based therapy in human renal transplantation: similar efficacy and different toxicity compared with cyclosporine: Sirolimus European Renal Transplant Study Group. Transplantation 1999;67:1036e42. [14] Elloso MM, Azrolan N, Sehgal SN, et al. Protective effect of the immunosuppressant sirolimus against aortic atherosclerosis in apo E-deficient mice. Am J Transplant 2003;3:562e9. [15] Vincenti F, Larsen C, Durrbach A, et al., for the Belatacept Study Group. Costimulation blockade with belatacept in renal transplantation. N Engl J Med 2005;353:770e81. [16] Franz S, Regeniter A, Hopfer H, et al. Tubular toxicity in sirolimus- and cyclosporine-based transplant immunosuppression strategies: an ancillary study from a randomized controlled trial. Am J Kidney Dis 2010;5:335e43. [17] Van Ree RM, Oterdoom LH, de Vries AP, et al. Circulating markers of endothelial dysfunction interact with proteinuria in predicting mortality in renal transplant recipients. Transplantation 2008;86:1713e9.
ABSTRACT Background. Cardiovascular disease (CVD) is the second major cause of death in kidney-transplanted children. Cardiovascular risk factors (CVRF) prevalence after transplant may increase. The effect of immunosuppressive therapy has not been fully studied in children. The objective of the study was to measure and compare CVRF prevalence in kidney-transplanted children, depending of immunosuppressive therapy. Methods. The study was an observational, transversal, retrospective, comparative study of pediatric patients transplanted at UMAE Hospital General Centro Medico La Raza. All patients were treated with prednisone and mycophenolic acid and any of cyclosporine, tacrolimus, or sirolimus. Demographic, clinical, and biochemical variables and immunosuppressive therapy were evaluated. We used analysis of variance, c2, and Fisher tests with the SPSS 18.0 statistical program. Results. One hundred fifteen patients were studied. Sixty-five (56.5%) were male, and median age was 18.5 2.3 years. Seventy-eight (67.2%) were transplanted from a living related donor. Prevalence of anemia and nephrotic proteinuria was significantly less in patients treated with tacrolimus. Those treated with cyclosporine had a significantly greater prevalence of increased LDL-cholesterol, increased serum phosphorus, and increased calcium-phosphorus. Those treated with tacrolimus had lower, not significant, prevalence of hypertension, hyperuricemia, hypoalbuminemia, hypercholesterolemia, hypertriglyceridemia, and low serum HDL-cholesterol than those treated with sirolimus and cyclosporine. In multivariate analysis, patients treated with cyclosporine had significantly more probability of increased phosphorus (OR, 10.65; 95% CI, 2.75e41.16, P ¼ .001) and calcium-phosphorus (OR, 37.94; 95% CI, 3.45e416.17, P ¼ .003) than those treated with tacrolimus. Conclusions. Patients treated with tacrolimus had less prevalence of CVRF than those treated with cyclosporine or sirolimus. Tacrolimus is the best immunosuppressive option to diminish CVRF in children after kidney transplantation.
C
HRONIC RENAL DISEASE (CKD) is a public health problem around the world, and its incidence and prevalence is increasing, as well as the costs. K/DOQI guidelines define CKD as “renal damage for 3 or more months defined by structural or functional abnormalities with or without decrease in glomerular filtration rate (GFR) manifested by histopathological abnormalities or with presence of renal damage markers including abnormalities in blood or urine composition, or image tests; or as GFR <60 mL/min/1.73 m2 body surface (BS) for 3 or more months with or without renal damage” [1]. ª 2016 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
Transplantation Proceedings, 48, 639e642 (2016)
In the United States, children 0 to 19 years old account for 1% of patients treated with dialysis, according to data from United States Renal Disease Statistics (USRDS). In 2007, 1245 children, 14.5 per million of habitants, began
*Address correspondence to Juan Antonio García-Bello, Department of Pediatric Nephrology, UMAE Hospital General Centro Médico La Raza, Instituto Mexicano del Seguro Social, México City, Mexico. E-mail: [email protected] 0041-1345/16 http://dx.doi.org/10.1016/j.transproceed.2016.02.034
639
640
GARCÍA-BELLO, ROMO-DEL RÍO, MENDOZA-GÓMEZ ET AL Table 1. Biochemical Characteristics of Kidney-Transplanted Patients, Depending on Immunosuppression Therapy Used
Variable
Total n ¼ 115 Value (SD)
Hemoglobin, g/dL Uric acid, mg/dL Albumin, g/dL Total cholesterol, mg/dL Triglycerides, mg/dL HDL-cholesterol, mg/dL LDL-cholesterol, mg/dL Calcium, mg/dL Phosphorus, mg/dL Calcium phosphorus Proteinuria, mg/m2/h‡ Cr Cl, mL/min/1.73 m2 SC
13.71 2.41 6.12 1.61 4.62 0.41 167.77 38.75 141.33 66.63 49.37 17.74 132.27 37.75 9.62 0.74 2.70e6.80 (1.27) 40.99 (9.89) 5.60 (6.00) 83.99 43.21
Tacrolimus n ¼ 78 Value (SD)
13.96 5.87 4.70 161.43 138.50 52.24 122.36 9.67 4.13 40.03 4.83 87.12
Sirolimus n ¼ 18 Value (SD)
(2.34) (1.65) (0.41)* (33.51) (66.37) (15.44) (35.54)* (0.80) (0.82)* (8.82)* (4.67)† (42.39)
13.14 6.76 4.35 184.05 162.94 38.50 137.82 9.44 3.95 36.61 19.58 65.19
(2.55) (1.34) (0.33)* (45.59) (75.56) (32.66) (31.81) (0.39) (1.03)† (9.49)† (21.65)† (28.71)
Cyclosporine n ¼ 19 Value (SD)
13.21 6.53 4.59 174.10 132.78 45.92 169.01 9.62 5.09 49.04 6.62 92.80
(2.51) (1.54) (0.32) (44.48) (59.61) (19.48) (28.81)* (0.73) (1.02)*,† (10.49)*,† (6.7)† (51.83)
P Value
.265 .051 .004 .051 .315 .606 <.001 .505 <.001 <.001 .001 .097
Values are presented as means and standard deviations or medians with interquartile intervals. *,†P values <.05 between groups (post hoc Bonferroni test). ‡ ANOVA or Kruskal-Wallis tests were used.
substitutive treatment for CKD, and 7209 children, 84.6 per million of habitants, were receiving such treatment (USRD, 2011). In Mexico in 2008, there were more than 120,000 patients with terminal CKD; 15,000 were children [2]. Cardiovascular disease (CVD) is major cause of death in patients with CKD. In pediatric patients in 2002, USRDS data show that CVD was the death cause in 8549 pediatric patients on chronic dialysis, accounting for 27% of death causes. In transplanted patients, CVD was the death cause in 22% patients in 2011 [3]. Traditional cardiovascular risk factors (CVRF) have been identified in adults such as age, male sex, hypertension, diabetes, lipid disturbances, and physical inactivity. CVRF related to CKD are added: anemia, hypervolemia, and hyperparathyroidism. CVRF related to treatment modality increases morbidity and mortality, such as glucose overload in peritoneal dialysis patients [4]. Children usually have no diabetes, smoking, or age effects and therefore they deserve separate studies. Although renal transplantation (RT) is the treatment of choice for CKD patients, it does not lower CVD prevalence or prevalence of CVRF. In children, it appears that CVRF increases after successful RT [5]. Between multiple causes of CVD in renal-transplanted children, most of immunosuppressive drugs used have secondary effects on cardiovascular risk. Calcineurin inhibitors such as cyclosporine and tacrolimus cause hypertension. mTOR inhibitors induce dyslipidemia. Corticosteroids and tacrolimus predispose to insulin resistance and affect insulin synthesis, which can generate development of diabetes [6]. To date, we do not know the impact of the kind of immunosuppression on prevalence of cardiovascular risk factors in the pediatric patients transplanted at our hospital. The objective of the study was to measure and compare the prevalence of cardiovascular risk factors in kidney-transplanted children according to received immunosuppression.
METHODS The study was an observational, transversal, retrolective, comparative study of children 6 to 21 years old transplanted before the age of 16 years in Hospital General Centro Medico La Raza. We evaluated sex, age, CKD etiology, nutritional status considering malnourished to patients in whom height zeta score was under 2, and overweight or obesity to patients who satisfied criteria of International Obesity Task Force (IOFT) according their body mass index for age and sex [7]. Patients were considered as hypertensive when systolic or diastolic pressure was greater than 95 percentile for sex, age, and height percentile according to validated values of the American Heart Association [8,9]. After patient fasting, we measured hemoglobin, calcium, phosphorus, albumin, total cholesterol, triglycerides, HDLcholesterol, LDL-cholesterol, and uric acid by use of the colorimetric method in the automatized method with Modular PP (Roche Diagnostics, Japan). Low albumin was considered when <4 g/dL. According to the National Cholesterol Educational Program [10], triglyceride levels were considered elevated when 110 mg/dL, low HDL-cholesterol when <40 mg/dL, and elevated LDL-cholesterol when 110 mg/dL. Elevated uric acid was considered when it was superior to normal level for age. Corrected calcium was calculated as Ca (mg/dL) þ 0.8 (4 albumin in mg/dL) and compared with K/DOQI guidelines. Phosphorus was defined as low, normal, or elevated according to validated tables [11]. The calciumphosphorus index was stratified according to K/DOQI guidelines: for children age >13 years as abnormal when >55 or normal when &55, and for children 6 to 12 years old, abnormal when >65 and normal when &65. Creatinine clearance was measured and stratified according to K/DOQI guidelines. Proteinuria was considered when >4 mg/m2/h and nephrotic proteinuria when >40 mg/m2/h. Means with standard deviations, medians with interquartile intervals, frequencies, and proportions for descriptive statistics were calculated. The c2, Fisher test, and analysis of variance (ANOVA) were used to determine if association existed for variables with immunosuppressive therapy. The SPSS 18.0 statistic program was used, and P values <.05 were considered significant.
RESULTS
One hundred fifteen patients were studied. Sixty-five (56.5%) were male, with mean age 18.5 2.3 years. Time
IMMUNOSUPPRESSIVE THERAPY IN KIDNEY-TRANSPLANTED CHILDREN
641
Table 2. Cardiovascular Risk Factor Prevalence in Kidney-Transplanted Patients, Depending on Immunosuppression Therapy Used Risk Factor
Desnutrition Overweight/obesity Hypertension Anemia Hyperuricemia Hypoalbuminemia Hypercholesterolemia Hypertriglyceridemia Low HDL-cholesterol Increased LDL-cholesterol Proteinuria Nephrotic proteinuria Decreased CrCl Hypercalcemia Hypocalcemia Hyperphosphatemia Increased Ca P
Total n ¼ 115
60 14 16 27 27 7 20 70 4 82 64 9 86 52 8 32 10
(52.1) (12.1) (13.9) (23.4) (23.4) (6.0) (17.3) (60.8) (3.4) (71.3) (55.6) (7.8) (74.7) (45.2) (6.9) (27.8) (8.6)
Tacrolimus n ¼ 78
40 9 7 13 16 3 10 45 1 49 41 3 57 40 7 15 3
Sirolimus n ¼ 18
(51.3%) (11.5%) (9.0%) (16.7%) (20.5%) (3.8%) (12.8%) (57.7%) (11.1%) (62.8%) (52.6%) (3.8%) (73.1%) (51.3%) (9.0%) (19.2%) (3.8%)
from transplant was 50.73 34.95 months. Table 1 shows variable values in all patients and according to immunosuppression received. Table 2 shows the prevalence of cardiovascular risk factors in all patients and according to immunosuppression received. Anemia prevalence and nephrotic proteinuria were significantly less in tacrolimus-treated patients. Those treated with cyclosporine had significantly higher prevalence of increased LDL-cholesterol, increased phosphorus, and increased calcium-phosphorus product. Those treated with tacrolimus had less, but not statistically significant, prevalence of hypertension, increased uric acid, low serum albumin, increased total cholesterol, increased triglycerides, and low HDL-cholesterol, than those treated with sirolimus and cyclosporine. In multivariate analysis adjusted for sex, age, nutritional status, proteinuria, and CKD stage, patients treated with cyclosporine showed significantly more probability of increased phosphorus (OR, 10.65; 95% CI, 2.75e41.16; P ¼ .001) and calcium-phosphorus (OR, 37.9; 95% CI; 3.45e416.17, P ¼ .003) than those treated with tacrolimus. No other significant association was found (Table 3).
8 5 5 8 6 2 6 13 1 14 12 4 13 5 0 4 1
(44.4%) (27.8%) (27.8%) (44.4%) (33.3%) (11.1%) (33.3%) (72.2%) (50.0%) (77.8%) (66.7%) (22.2%) (72.2%) (27.8%) (0.0%) (22.2%) (5.6%)
Cyclosporine n ¼ 19
12 0 4 6 5 2 4 12 2 19 11 2 16 7 1 13 6
(63.2%) (0.0%) (21.1%) (31.6%) (26.3%) (10.5%) (21.1%) (63.2%) (40.0%) (100%) (57.9%) (10.5%) (74.8%) (36.8%) (5.3%) (68.4%) (31.6%)
P Value
.138 .071 .029 .487 .344 .106 .510 .334 .005 .022 .447 .106 .001 .001
DISCUSSION
The prevalence of cardiovascular risk factors was not different from that reported by other authors. In our study, there was no significant difference in prevalence of hypertension according to immunosuppression used, but, in those treated with sirolimus and cyclosporine, the prevalence of hypertension was over the mean of all patients. The mechanism for cyclosporine-induced hypertension is not fully understood, but many have been implicated. Gordjani et al [12] showed a significant association between cyclosporine trough levels and hypertension. Calcineurin inhibitors can induce hypertension by afferent arteriolar vasoconstriction, sodium and water retention, sympathetic overactivity, renin system stimulation, and impaired nitric oxideedependent vasodilatation. Anti-mTOR agents produce dyslipidemia in a dosedependent way that may contribute to development of cardiovascular disease after transplantation [13]. Nevertheless, in the atheromatosis animal model, sirolimus administration was able to reduce 50% of aortic atheromatous lesions. That was accompanied by less expression of interleukins (IL) implicated in the atheromatous process (IL-10) versus the control group
Table 3. Multivariate Analysis (Logistic Regression) Immunosuppressive
Tacrolimus Sirolimus
Cyclosporine
Risk Factor
OR
95% CI
P Value
Increased LDL-cholesterol Hyperphosphatemia Increased Ca P Hypoalbuminemia Increased LDL-cholesterol Hyperphosphatemia Increased Ca P Hypoalbuminemia
1.00 3.45 1.25 4.27 1.90 1.86 10.65 37.94 2.39
0.66e18.07 0.26e6.05 0.19e96.50 0.21e17.04 0.001e109.54 2.75e41.16 3.45e416.17 0.29e19.25
.141 .777 .361 .564 .998 .001 .003 .413
Variables included age, sex, nutritional status, proteinuria, CKD stage.
642
[14]. Although in previous studies there were no differences in serum lipid levels between belatacept and cyclosporine, more patients in the cyclosporine group required treatment with lipid-lowering medications [15]. Anti-mTOR agents can generate proteinuria, particularly in patients with previous renal damage [16]. This proteinuria is a predictor of endothelial dysfunction and mortality in transplanted patients [17]. We found no previous studies reporting calcium phosphorus to be different among patients treated with specific immunosuppressive agents. In summary, in our study, patients treated with tacrolimus had a minor prevalence of most cardiovascular risk factors compared with those treated with cyclosporine or sirolimus. Significant association of immunosuppressive agent was found only with anemia, serum albumin, proteinuria, and increased LDL-cholesterol, phosphorus, and calciumphosphorus product. In multivariate analysis, patients treated with sirolimus showed significantly more probability of increased phosphorus and calcium-phosphorus than those treated with cyclosporine. Tacrolimus was the better option for immunosuppression to decrease cardiovascular risk in studied patients. In pediatric transplanted patients, in which cardiovascular disease is still the second cause of death, to avoid drug-induced risk is primordial, and to choose the best immunosuppression is primordial.
REFERENCES [1] National Kidney Foundation. NKF/DOQI Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation, Classification and Stratification. Am J Kidney Dis 2002;39(Suppl 1):S1e266. [2] General Direction of Information in Health. Mexico City: Health Department & National Institute of Statistics and Geography; 2008. [3] US Renal Data System: USRDS 2011 Annual Data Report: Atlas of Chronic Kidney Disease and End-Stage Renal Disease in the United States. Bethesda, Maryland: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 2011.
GARCÍA-BELLO, ROMO-DEL RÍO, MENDOZA-GÓMEZ ET AL [4] Goicoechea M, de Vinuesa SG, Gómez-Campderá F, Luño J. Predictive cardiovascular risk factors in patients with chronic kidney disease. Kidney Int 2005;67(Suppl 93):S35e8. [5] Mitsnefes MM. Cardiovascular disease in children with chronic kidney disease. J Am Soc Nephrol 2012;23:578e85. [6] Marques Vidas M, Lopez Lafuente J. Cardiovascular disease in kidney transplantation. Clinical Hospital, San Carlos, Madrid, and University Hospital, Alcorcon, Madrid. 2008;15:149e58. [7] Cole E, Levey A, Kurian SM, et al. Chronic kidney disease as a global health problem in public medical care: approach and initiative-proposals of Kidney Disease Improving Global Outcomes. Kidney Int 2007;3:232e45. [8] National High Blood Pressure Education Program Working Group on Hypertension Control in Children and Adolescents. Update on the 1987 Task Force on High Blood Pressure in children and adolescents: a working group report from the National High Blood Pressure Education Program. Pediatrics 1996;98:649e58. [9] Falkner B, Daniels SR. Summary of the Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and Adolescents. Hypertension 2004;44:387e8. [10] National Cholesterol Education Program (NCEP): highlights of the report of the Expert Panel on Blood Cholesterol Levels in Children and Adolescents. Pediatrics 1992;89:495e501. [11] Gunn IR. Biological variation of serum and urine creatinine and creatinine clearance. Ann Clin Biochem 1999;26:302e3. [12] Gordjani N, Offner G, Hoyer PF, Brodehl J. Hypertension after renal transplantation in patients treated with cyclosporine and azathioprine. Arch Dis Child 1990;65:275e9. [13] Groth CG, Bäckman L, Morales JM, et al. Sirolimus (rapamycin)-based therapy in human renal transplantation: similar efficacy and different toxicity compared with cyclosporine: Sirolimus European Renal Transplant Study Group. Transplantation 1999;67:1036e42. [14] Elloso MM, Azrolan N, Sehgal SN, et al. Protective effect of the immunosuppressant sirolimus against aortic atherosclerosis in apo E-deficient mice. Am J Transplant 2003;3:562e9. [15] Vincenti F, Larsen C, Durrbach A, et al., for the Belatacept Study Group. Costimulation blockade with belatacept in renal transplantation. N Engl J Med 2005;353:770e81. [16] Franz S, Regeniter A, Hopfer H, et al. Tubular toxicity in sirolimus- and cyclosporine-based transplant immunosuppression strategies: an ancillary study from a randomized controlled trial. Am J Kidney Dis 2010;5:335e43. [17] Van Ree RM, Oterdoom LH, de Vries AP, et al. Circulating markers of endothelial dysfunction interact with proteinuria in predicting mortality in renal transplant recipients. Transplantation 2008;86:1713e9.