Blood Pressure Elevation in Long-Term Survivors of Pediatric Liver Transplantation

As pediatric liver transplant (LT) recipients come of age, additional insight into long-term medical complications of immunosuppression is warranted. The aims of this study were to estimate the prevalence of elevated blood pressure (BP) in long-term survivors of pediatric LT using the data from the Studies in Pediatric Liver Transplantation (SPLIT) database and to identify predictive factors. Patients enrolled in the BP arm of the SPLIT cohort participated in the study. All patients were of at least 5 years but ≤10 years post-LT. Automated BP measurements were obtained at anniversary visits. BP measures were classified as normal, borderline or elevated according to standard criteria. Patients taking antihypertensive medications were classified as “elevated.” Eight hundred and fifteen patients participated. The prevalence of elevated BP measurements 5 to 10 years post-LT was 17.5 to 27.5%. Of total 62.5% patients presented with at least one additional elevated BP at a later follow up visit. Multivariate analysis revealed the following parameters to be predictive of elevated BP: age at transplant, steroid use at last BP measurement and cGFR at last BP measurement. Pediatric LT patients show a high prevalence of elevated BP measurements 5 to 10 years following LT, which is related to age at LT, decreased cGFR and recent steroid use. As pediatric liver transplant (LT) recipients come of age, additional insight into long-term medical complications of immunosuppression is warranted. The aims of this study were to estimate the prevalence of elevated blood pressure (BP) in long-term survivors of pediatric LT using the data from the Studies in Pediatric Liver Transplantation (SPLIT) database and to identify predictive factors. Patients enrolled in the BP arm of the SPLIT cohort participated in the study. All patients were of at least 5 years but ≤10 years post-LT. Automated BP measurements were obtained at anniversary visits. BP measures were classified as normal, borderline or elevated according to standard criteria. Patients taking antihypertensive medications were classified as “elevated.” Eight hundred and fifteen patients participated. The prevalence of elevated BP measurements 5 to 10 years post-LT was 17.5 to 27.5%. Of total 62.5% patients presented with at least one additional elevated BP at a later follow up visit. Multivariate analysis revealed the following parameters to be predictive of elevated BP: age at transplant, steroid use at last BP measurement and cGFR at last BP measurement. Pediatric LT patients show a high prevalence of elevated BP measurements 5 to 10 years following LT, which is related to age at LT, decreased cGFR and recent steroid use. Pediatric liver transplantation (LT) has transformed the prognosis of children with acute or chronic liver disease. It is now the therapeutic modality of choice in children with end-stage liver disease and excellent long-term survival is the expected norm (1Wallot MA Mathot M Janssen M et al.Long-term survival and late graft loss in pediatric liver transplant recipients—A 15-year single-center experience.Liver Transpl. 2002; 8: 615-622Crossref PubMed Scopus (104) Google Scholar,2Ng VL Fecteau A Shepherd R et al.Outcomes of 5-year survivors of pediatric liver transplantation: Report on 461 children from a north american multicenter registry.Pediatrics. 2008; 122: e1128-e1135Crossref PubMed Scopus (182) Google Scholar). Long-term patient and graft survival is largely attributable to the advent of efficacious immunosuppression (3Calne RY Rolles K White DJ et al.Cyclosporin A initially as the only immunosuppressant in 34 recipients of cadaveric organs: 32 kidneys, 2 pancreases, and 2 livers.Lancet. 1979; 2: 1033-1036Abstract PubMed Scopus (841) Google Scholar, 4Calne RY Rolles K White DJ et al.Cyclosporin A in clinical kidney grafting from cadaver donors.Proc Eur Dial Transplant Assoc. 1979; 16: 305-309PubMed Google Scholar, 5White DJ Calne RY Plumb A Mode of action of cyclosporin A: A new immunosuppressive agent.Transplant Proc. 1979; 11: 855-859PubMed Google Scholar, 6Zimmermann FA White DJ Gokel JM Calne RY Orthotopic liver transplantation in rats. Prolonging of survival time of allotransplants using cyclosporin A in an acute rejection model.Chir Forum Exp Klin Forsch. 1979; : 339-344PubMed Google Scholar, 7Mells G Neuberger J Reducing the risks of cardiovascular disease in liver allograft recipients.Transplantation. 2007; 83: 1141-1150Crossref PubMed Scopus (62) Google Scholar). However, it is now well recognized that long-term immunosuppression carries its own set of risks. Among them, hypertension, diabetes mellitus, dyslipidemia and nephrotoxicity have been identified as major causes of late mortality among adult liver transplant recipients (2Ng VL Fecteau A Shepherd R et al.Outcomes of 5-year survivors of pediatric liver transplantation: Report on 461 children from a north american multicenter registry.Pediatrics. 2008; 122: e1128-e1135Crossref PubMed Scopus (182) Google Scholar,8Davidson J Wilkinson A Dantal J et al.New-onset diabetes after transplantation: 2003 international consensus guidelines. In: Proceedings of an International Expert Panel Meeting. 19 February 2003; Barcelona, Spain.Transplantation. 2003; 75: SS3-SS24PubMed Google Scholar, 9Reuben A Long-term management of the liver transplant patient: Diabetes, hyperlipidemia, and obesity.Liver Transpl. 2001; 7: S13-S21Crossref PubMed Scopus (107) Google Scholar, 10Ader JL Rostaing L Cyclosporin nephrotoxicity: Pathophysiology and comparison with FK-506.Curr Opin Nephrol Hypertens. 1998; 7: 539-545Crossref PubMed Scopus (52) Google Scholar, 11Kobashigawa JA Kasiske BL Hyperlipidemia in solid organ transplantation.Transplantation. 1997; 63: 331-338Crossref PubMed Scopus (280) Google Scholar). The prevalence of arterial hypertension in adult transplant recipients (solid organ, excluding kidney) has been reported to be between 10% and 50% (12Textor SC Taler SJ Canzanello VJ Schwartz L Augustine JE Posttransplantation hypertension related to calcineurin inhibitors.Liver Transpl. 2000; 6: 521-530Crossref PubMed Scopus (117) Google Scholar). Little is known about the prevalence of hypertension and other cardiovascular risk factors among pediatric transplant recipients, yet this population caries the risks of greater cumulative exposure to immunosuppressants and their side effects. Studies in adults have shown that liver transplant recipients have a 2.5-fold greater risk of cardiovascular mortality and threefold greater risk of ischemic events than does a matched, untransplanted population (13Johnston SD Morris JK Cramb R Gunson BK Neuberger J Cardiovascular morbidity and mortality after orthotopic liver transplantation.Transplantation. 2002; 73: 901-906Crossref PubMed Scopus (281) Google Scholar). It is unclear whether these findings can be extrapolated to the pediatric population. A few reports suggest that following solid organ transplantation, children also have cardiovascular and metabolic abnormalities (14McDiarmid SV Gornbein JA Fortunat M et al.Serum lipid abnormalities in pediatric liver transplant patients.Transplantation. 1992; 53: 105-109Crossref Scopus (44) Google Scholar,15Smith JM Nemeth TL McDonald RA Current immunosuppressive agents in pediatric renal transplantation: Efficacy, side-effects and utilization.Pediatr Transplant. 2004; 8: 445-453Crossref PubMed Scopus (30) Google Scholar). Others suggest that younger patients may spontaneously normalize their blood pressures (BPs) (12Textor SC Taler SJ Canzanello VJ Schwartz L Augustine JE Posttransplantation hypertension related to calcineurin inhibitors.Liver Transpl. 2000; 6: 521-530Crossref PubMed Scopus (117) Google Scholar). It is accepted that posttransplant hypertension is primarily attributable to immunosuppression and renal disease, although there may be other, unrecognized risk factors. The prevalence of elevated BP in long-term pediatric liver transplant recipients is not known, something which this study aims to address by focusing on BP data from the patients enrolled in the Studies in Pediatric Liver Transplantation (SPLIT) registry. Children with hypertension have a 2.5-fold increased risk of becoming adults with hypertension (16Lauer RM Clarke WR Childhood risk factors for high adult blood pressure: The Muscatine Study.Pediatrics. 1989; 84: 633-641Crossref PubMed Google Scholar) and it is now accepted that end organ damage secondary to hypertension is a measurable problem in pediatrics (17McNiece KL Poffenbarger TS Turner JL et al.Prevalence of hypertension and pre-hypertension among adolescents.J Pediatr. 2007; 150 (644 e1.): 640-644Abstract Full Text Full Text PDF PubMed Scopus (454) Google Scholar, 18Daniels SR Loggie JM Khoury P Kimball TR Left ventricular geometry and severe left ventricular hypertrophy in children and adolescents with essential hypertension.Circulation. 1998; 97: 1907-1911Crossref PubMed Scopus (331) Google Scholar, 19Berenson GS Srinivasan SR Bao W et al.Association between multiple cardiovascular risk factors and atherosclerosis in children and young adults. The Bogalusa heart study.N Engl J Med. 1998; 338: 1650-1656Crossref PubMed Scopus (3128) Google Scholar). Hypertension has been shown to be an independent risk factor of renal insufficiency in both adult and pediatric liver transplant recipients (20Harambat J Ranchin B Dubourg L et al.Renal function in pediatric liver transplantation: A long-term follow-up study.Transplantation. 2008; 86: 1028-1034Crossref PubMed Scopus (59) Google Scholar,21Canzanello VJ Textor SC Taler SJ et al.Late hypertension after liver transplantation: A comparison of cyclosporine and tacrolimus (FK 506).Liver Transpl Surg. 1998; 4: 328-334Crossref PubMed Scopus (70) Google Scholar) and is one of the leading causes of end-stage renal disease in adults (22System URD USRDS 2004; Annual Data Report. 2004.Google Scholar). Thus, the aims of this study were to estimate what proportion of long-term LT patients have elevated BP and to identify predictors of developing elevated BP between 5 and 10 years posttransplant. Ultimately, knowing the prevalence and risk factors of elevated BP in pediatric liver transplant recipients should help transplant physicians and pediatricians identify those children with hypertension and direct medical intervention in a timely and cost-effective fashion to avoid severe, long-term complications. Data were obtained from patients enrolled in SPLIT database. The SPLIT database is a registry of pediatric patients having been evaluated for liver transplantation, which was initiated in 1995. It includes prospectively collected data on all patients under the age of 18 years from the time of their first evaluation for transplant until the subjects reach the age of 18. Data are collected at anniversary visits at each of 42 participating centers across Canada and the United States and submitted to a central data-coordinating center whose role is to monitor and evaluate data quality. The institutional review board of each participating center evaluates and approves the SPLIT data-collecting protocol. Consent is obtained from parents or legal guardians at the time of listing for liver transplantation. For the purposes of this study, only patients one transplant and were years of age by and between 5 and 10 years posttransplant. The was that patients in this age be for BP the of this study was to evaluate the risk factors of BP following transplant, the data 5 to 10 years posttransplant. Patients with kidney disease were from this study of their risk for Patients with other with kidney as were not these are with hypertension in the pediatric age and a of the of BP measurements in the patients years of age in BP measurement was obtained for all children age 5 years or using a at the at follow up for the first 2 years post-LT and For the purposes of this study, BP was as and pressure for age and or is BP was as a or BP for age and BP was as a or BP between and for age and on the and of high blood pressure in children and 2004; Google Scholar). The accepted of hypertension in pediatrics is BP or at at least on the and of high blood pressure in children and 2004; Google Scholar). The accepted of is BP or between and for age on the and of high blood pressure in children and 2004; Google Scholar). The hypertension be in this study, BP measurements were obtained for the patients in the borderline or elevated A was to the of the and data M et of elevated blood pressure among children and Data from the and J Hypertens. PubMed Scopus Google BL et for the study and of elevated blood pressure in with diabetes The for diabetes in Pediatr. Full Text Full Text PDF PubMed Scopus Google Scholar). Thus, a was anniversary 5 years or which the patient a BP measurement or BP medications Patients on antihypertensive medications were to have was using the at each BP A The use of for in and PubMed Scopus Google Scholar). were using the for for age, for age and were in to and as were BP of and et United 2000; Google Scholar). The SPLIT registry has been patients prospectively 1995. For the purposes of this study, data were collected up to and at which time the registry those patients enrolled in the BP arm of the registry were for the study. The BP arm was initiated in and includes patients greater than 5 years of age of time the of study was to long-term on those patients the in the Eight hundred and fifteen patients at least one at which a BP measurement was obtained or antihypertensive use was these patients were the study population. and are in by age there were as age at transplant the of patients transplantation for decreased in the age and in the age the of patients liver for of increased and for patients with BP visits between 5 and 10 years cohort or liver at transplant in a new the prevalence of elevated BP measurements in the study population at The of normal, borderline and elevated BP measurements was between 17.5 and of patients were taking antihypertensive medications or at least one BP as for age, and measurements were obtained in to of to of patients were not on antihypertensive medications and not have a BP measurement the hundred and patients were taking antihypertensive medications in the to there is between the of patients with elevated BP at 10 years posttransplant and time the a prevalence of elevated BP or antihypertensive use in this which increased of elevated BP with time Of the patients at least one BP at least in the to time Of at least one elevated BP measurement a BP visit. hundred patients a follow-up measurement an BP was Among at least elevated BP measurement after the first that in children with an elevated BP measurement at follow up visits as as have at least elevated BP measurement. of patients in a BP measurement is obtained not have elevated findings are in The data of the patients were for predictors of long-term risk of elevated BP the of risk factors by BP at last BP measurement between 5 and 10 years posttransplant. analysis was to identify predictors of at least one elevated BP in children years of age and 5 to 10 years following The following factors which were in a analysis with age at transplant use of at last BP cGFR elevated BP age at last time from transplant not reach in the it was in the for it as a for time transplant, which is to age in the pediatric population. it as a for cumulative calcineurin elevated BP was from the analysis only children BP is to the of patients having children between 5 and years and having 5 years these patients have than one BP The that parameters the of having an elevated BP measurement late in posttransplant follow-up age at transplant years and years a greater risk of elevated BP measurement to patients years at the time of steroid exposure at the time of the last BP measurement increased the risk of elevated cGFR at last BP measurement also increased the risk of an elevated BP cGFR a threefold in the of an elevated BP measurement between 5 and 10 years following time from transplant, as a not reach in this were in the risk of elevated BP in the to the increased of to to elevated for of renal or rejection in this age there was in of these complications with other age the between renal and elevated BP in greater whether cGFR elevated BP or whether elevated BP be a of cGFR between 5 and 10 years post-LT. on the the analysis data that in this elevated BP may the of renal in patients are accepted as the of posttransplant BP and renal to whether BP 5 to 10 years LT was related to cumulative to of SPLIT data were only to anniversary as a for As BP as a function of of visits with tacrolimus or cyclosporine or of visits with tacrolimus or not an of exposure on BP 5 to 10 years post-LT using this also BP according to of years of use. was of of years on BP exposure and time transplant were not are also accepted to be major to use at the time of BP measurement was a of elevated BP both in and As a analysis to and cumulative steroid the of the SPLIT database. first whether use in the first 2 years following LT long-term BP but was as a for cumulative steroid whether visits with steroid use increased the risk of elevated BP to a there was greater risk of an elevated BP with steroid exposure study that elevated BP measurements in as as of pediatric LT patients 5 years or and at least 5 years post-LT. It a of younger age at transplant the of steroid use and an with cGFR that pediatric hypertension to the of adult cardiovascular disease and that children are to damage SR Loggie JM Khoury P Kimball TR Left ventricular geometry and severe left ventricular hypertrophy in children and adolescents with essential hypertension.Circulation. 1998; 97: 1907-1911Crossref PubMed Scopus (331) Google Scholar). this analysis should to pediatricians as well as following these patients in a to evaluate BP and other cardiovascular risk factors to children are the age of to be from the risk of long-term BP as to those in have this on that younger patients have a of hypertension than patients (12Textor SC Taler SJ Canzanello VJ Schwartz L Augustine JE Posttransplantation hypertension related to calcineurin inhibitors.Liver Transpl. 2000; 6: 521-530Crossref PubMed Scopus (117) Google for the that children after the age of may than their between the of 5 and a which a of this the role of age at transplant in the to elevated BP is the age years is of than of age are in for and have been shown to be to hypertension (20Harambat J Ranchin B Dubourg L et al.Renal function in pediatric liver transplantation: A long-term follow-up study.Transplantation. 2008; 86: 1028-1034Crossref PubMed Scopus (59) Google Scholar). The analysis these findings age at LT the risk of having an elevated BP measurement later in Thus, that the between the 5 and age and the may be an patient is between age that the of in their first of may be from long-term posttransplant elevated the other the of steroid use on long-term BP is to be hypertension is accepted to be a of use of disease or Thus, in BP or intervention in the of patients on is until the end of the steroid However, the use of as at 2 or visits an increased risk of long-term BP it may be to hypertension by in patients long-term for as rejection or posttransplant in these help long-term renal (22System URD USRDS 2004; Annual Data Report. 2004.Google A factors for of chronic kidney Opin Pediatr. PubMed Scopus Google Scholar). The of for the of posttransplant complications is in the management of these time transplant not reach in the there to be a in that It is unclear whether this is to at 10 or whether of exposure to and other agents BP is of a problem than be the measures for cumulative exposure in this were not with an increased risk of elevated BP long-term post-LT. of cumulative the greater factor is that not to to elevated BP measurements in this Hypertension to of in adults and children with or a of solid organ transplantation (22System URD USRDS 2004; Annual Data Report. 2004.Google A factors for of chronic kidney Opin Pediatr. PubMed Scopus Google Scholar, M et and blood pressure as of to end-stage renal study Dial Transplant. 11: PubMed Google Scholar, BL et pressure and end-stage renal disease in Engl J Med. PubMed Scopus Google Scholar, M Hypertension and of chronic renal insufficiency in A of the north american pediatric renal transplant study 2003; PubMed Scopus Google Scholar, study of a on the of chronic renal in study of of chronic renal in 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). pediatric LT recipients, it has been shown that hypertension is predictive of long-term renal insufficiency (20Harambat J Ranchin B Dubourg L et al.Renal function in pediatric liver transplantation: A long-term follow-up study.Transplantation. 2008; 86: 1028-1034Crossref PubMed Scopus (59) Google Scholar). cGFR at the time of BP was a of elevated BP measurements in patients between 5 and 10 years something which to the of has not been reported at this data in greater that a elevated BP measurement later renal the findings of (20Harambat J Ranchin B Dubourg L et al.Renal function in pediatric liver transplantation: A long-term follow-up study.Transplantation. 2008; 86: 1028-1034Crossref PubMed Scopus (59) Google Scholar). However, findings should be with the of patients for this were this is that at BP one that elevated BP in patients with is to As a elevated BP or decreased should be a for physicians to a follow-up and of renal function and cardiovascular risk factors. a be for patients for hypertension not the for to from renal on the and of high blood pressure in children and 2004; Google KL JA Pediatric and for the PubMed Scopus Google Scholar, for arterial hypertension in children with kidney disease. J Scholar, R JK et of high blood pressure in children and of the of Hypertens. PubMed Scopus Google Scholar, A et and of renal in Engl J Med. PubMed Scopus Google Scholar). this is by a of this study is the first to at the long-term prevalence and predictive factors of elevated BP following pediatric liver transplantation, it has it the prevalence or risk factors of having elevated BP measurements at follow up visits than hypertension centers only one BP measurement using an than but recent pediatric suggest that this is a (17McNiece KL Poffenbarger TS Turner JL et al.Prevalence of hypertension and pre-hypertension among adolescents.J Pediatr. 2007; 150 (644 e1.): 640-644Abstract Full Text Full Text PDF PubMed Scopus (454) Google BL et for the study and of elevated blood pressure in with diabetes The for diabetes in Pediatr. Full Text Full Text PDF PubMed Scopus Google Scholar). be to a estimate of hypertension, BP measurements at visits than should have been obtained and to whether the patients hypertension evaluation and on the and of high blood pressure in children and 2004; Google Scholar). this is having or predictive factors that the as to which patient to up should a in the management of these Of a of patients with a elevated BP measurement normalize as was in this study, the for a to identify the BP arm of the SPLIT registry only children 5 years of age or at the time of BP measurement. were to with factors the first BP to age 5 in children as children younger than 5 years of age at an anniversary were from the BP study, are to whether posttransplant elevated BP long-term risk of elevated something which However, it is to that steroid use in the first 2 years following LT not patients at increased risk of long-term elevated it that as as of long-term pediatric liver transplant recipients may with elevated BP measurements using standard at an 5 to 10 years post-LT. Of these as as may be measurements the prevalence of elevated it is a in pediatric LT recipients than a pediatric population of in which the prevalence of hypertension has been to be (17McNiece KL Poffenbarger TS Turner JL et al.Prevalence of hypertension and pre-hypertension among adolescents.J Pediatr. 2007; 150 (644 e1.): 640-644Abstract Full Text Full Text PDF PubMed Scopus (454) Google BL et for the study and of elevated blood pressure in with diabetes The for diabetes in Pediatr. Full Text Full Text PDF PubMed Scopus Google Scholar). Among those that with an elevated BP measurement at one as as 62.5% have elevated BP measurement a 5-year time of the risk of hypertension and renal disease in both children and these patients and this the in Hypertension is a of morbidity and mortality in the adult population following liver transplantation. that pediatric LT patients well into and that the of children to complications is the long-term and complications of transplant is becoming the transplant physicians and pediatricians should to monitor for the of as hypertension and renal and patients to the and hypertension may morbidity and help the of following solid organ was by of the of and and The all the participating SPLIT The of this have of to as by the of may be in the of this with and rejection by age at of risk factors by BP at last BP measurement and between 5 and 10 years in the first 5 years and steroid use by age at cGFR at by last BP measurement and BP measurement at by cGFR at last BP analysis of elevated BP 5 to 10 years analysis of immunosuppressant use and elevated BP 5 to 10 years posttransplant is not for the or of by the than should be to the for the

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