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

2011; Elsevier BV; Volume: 12; Issue: 1 Linguagem: Inglês

10.1111/j.1600-6143.2011.03772.x

1600-6143

Valérie A. McLin, Ravinder Anand, Stephen R. Daniels, W. Yin, Estella M. Alonso,

Organ Transplantation Techniques and Outcomes

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, we only considered patients who had received one transplant and were ≥5 years of age by August 1, 2005 and between 5 and 10 years posttransplant. The rationale was that patients in this age group would be cooperative for BP measurements. Because the focus of this study was to evaluate the risk factors of BP elevation long term following transplant, we examined the data spanning 5 to 10 years posttransplant. Patients with autosomal recessive polycystic kidney disease (n = 7) were excluded from this study because of their inherent risk for hypertension. Patients with other diseases associated with kidney dysfunction, such as Alagille syndrome, were not excluded because these diseases are rarely associated with hypertension in the pediatric age group and represent a very small fraction of the cohort. Collection of standardized BP measurements in the patients ≥5 years of age began in 2005. One automated BP measurement was obtained for all children age 5 years or older using a size-appropriate cuff, at the pretransplant evaluation, at 6-month follow up periods for the first 2 years post-LT and then annually. For the purposes of this study, normal BP was defined as systolic and diastolic pressure <90% for gender, age and height or below 120/80 mmHg (whichever is lower). Elevated BP was defined as a systolic or diastolic BP ≥95th percentile adjusted for gender, age and height. Borderline BP was defined as a systolic or diastolic BP between 90th and 95th percentile adjusted for gender, age and height (23The fourth report on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents.Pediatrics. 2004; 114 (4th Report:): 555-576PubMed Google Scholar). The accepted definition of hypertension in pediatrics is BP ≥ 95% (systolic or diastolic) at three consecutive office visits, at least 1 week apart (23The fourth report on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents.Pediatrics. 2004; 114 (4th Report:): 555-576PubMed Google Scholar). The accepted definition of prehypertension is BP (systolic or diastolic) between 90% and 95% for age (23The fourth report on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents.Pediatrics. 2004; 114 (4th Report:): 555-576PubMed Google Scholar). The term hypertension cannot be used in this study, Because repeated BP measurements were rarely obtained for the patients in either the borderline or elevated categories. A similar approach was recently used to report the results of the National Health and Nutrition Examination Survey (NHANES) 1988–2006 data (24Ostchega Y Carroll M Prineas RJ et al.Trends of elevated blood pressure among children and adolescents: Data from the national health and nutrition examination survey1988–2006.Am J Hypertens. 2009; 22: 59-67Crossref PubMed Scopus (157) Google Scholar,25Rodriguez BL Liese DD Fujimoto AD et al.Imperatore G, for the SEARCH study group Prevalence and correlates of elevated blood pressure in youth with diabetes mellitus: The search for diabetes in youth study.J Pediatr. 2010; 157: 245-251Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar). Thus, a “BP visit” was any anniversary visit 5 years or more post-LT, during which the patient had a BP measurement or his BP medications recorded. Patients on antihypertensive medications were considered to have “elevated” BP. Calculated glomerular filtration rate (cGFR) was determined using the Schwarz formula at each BP visit (26Schwartz GJ Brion LP Spitzer A The use of plasma creatinine concentration for estimating glomerular filtration rate in infants, children, and adolescents.Pediatr Clin North Am. 1987; 34: 571-590Crossref PubMed Scopus (1510) Google Scholar). Statistical analyses were performed using the SAS System for Windows 9.01 (SAS Institute Inc., Cary, NC, USA). Standardized height for age, weight for age and BMI Z-scores were calculated in reference to age- and gender-specific normative charts, as were BP percentiles (Centers of Disease Control and Prevention – www.cdc.gov/growthcharts) (27Kuczmarski RJ Ogden CL Grummer-Strawn LM et al.CDC growth charts: United States.Adv Data. 2000; 314: 1-27PubMed Google Scholar). The SPLIT registry has been enrolling patients prospectively since 1995. For the purposes of this study, data were collected up to and including May 2008, at which time the registry included 2997 patients. Only those patients enrolled in the BP arm of the registry were considered for the study. The BP arm was initiated in August 1, 2005 and includes patients greater than 5 years of age regardless of time since transplant. Because the aim of our study was to examine long-term BP, we focused on those 823 patients who met the inclusion criteria stated in the “Methods” section. Eight hundred and fifteen patients had at least one visit at which a BP measurement was obtained or antihypertensive medication use was recorded (“BP visit”); these patients were considered the study population. Their demographic-, disease-, and transplant-characteristics are summarized in Table 1. When broken down by age group, there were two noticeable differences as age at transplant increased. First, the number of patients requiring transplantation for biliary atresia (BA) decreased (71.3% in the 8 year age group; Table S1). Second, the number of patients warranting liver replacement for inborn errors of metabolism increased slightly (Table S1).Table 1:Demographics and baseline characteristics for patients with BP visits between 5 and 10 years posttransplantRecipient characteristicsBP cohort (n)% or mean ± SDTotal815100.0GenderMale36244.4Female45355.6RaceWhite51062.6Black12615.5Hispanic10412.8Other715.7Primary diagnosisBiliary atresia41450.8Other cholestatic11814.5Fulminant liver failure8210.1Metabolic disease10813.3Cirrhosis465.6Age at transplant (year)8153.5 ± 4.0Height Z score639−1.5 ± 1.7Weight Z score741−1.1 ± 1.8Transplant characteristicsGraft typeLiving related15218.7Deceased whole41050.3Deceased reduced15318.8Deceased split8610.6Initial immunosuppressionCsA base22828.0Tac base47358.0Other759.2 Open table in a new tab Figure 1 illustrates the prevalence of elevated BP measurements in the study population at yearly intervals since transplant. The distribution of normal, borderline and elevated BP measurements was relatively constant over time: between 17.5 and 27.5% of patients were either taking antihypertensive medications or had at least one BP measured as >95th percentile for age, gender and height. Borderline measurements were obtained in 6.9 to 9.3% of patients, whereas 65 to 73.6% of patients were not on antihypertensive medications and did not have a BP measurement outside the normal range. One hundred and seventeen patients (14.4%) were taking antihypertensive medications in the 5- to 10-year bracket since LT. Although there is no statistically significant difference between the number of patients with elevated BP values at 10 years posttransplant and earlier time points, the trend suggests a slightly higher prevalence of elevated BP or antihypertensive medication use in this group, which might reflect increased likelihood of elevated BP with time since transplant. Of the 815 patients who had at least one BP visit, 502 had at least another visit in the 5- to 10-year time bracket. Of these, 159 had at least one elevated BP measurement recorded during a BP visit. One hundred fourteen patients had a follow-up measurement if an automated BP was elevated. Among these, 72 (63.2%) had at least another elevated BP measurement recorded after the first (Figure 2), suggesting that in children with an elevated automated BP measurement at yearly follow up visits as many as 63.2% will have at least another elevated BP measurement. Conversely, 37% of patients in whom a repeat, automated BP measurement is obtained will not have persistently elevated measures. These findings are summarized in Figure 2. The data of the 815 patients were analyzed for potential predictors of long-term risk of elevated BP measurements. Table S2 summarizes the distribution of risk factors by BP status at last BP measurement between 5 and 10 years posttransplant. Univariate analysis was performed to identify potential predictors of measuring at least one elevated BP in children >5 years of age and 5 to 10 years following LT. The following factors which reached significance (p < 0.1) were then included in a multivariate analysis with stepwise backward elimination: Primary diagnosis (nonbiliary atresia cholestatic disease), age at transplant (>1 year), African American ethnicity, use of steroids at last BP measure, cGFR <90 mL/min/1.73 m2, previously elevated BP measurement, age at last BP. Although time from transplant did not reach statistical significance in the univariate analysis, it was included in the multivariate modeling for two reasons. First, it serves as a correction for time since transplant, which is frequently close to chronological age in the pediatric population. Second, it serves as a surrogate for cumulative calcineurin inhibitor (CNI) exposure. Finally, previous elevated BP was removed from the analysis because only 313/815 children had repeat BP measurements. This is owing to the large number of patients having recently reached eligibility: children aged between 5 and 6 years and having just completed 5 years posttransplant; these patients cannot have had more than one BP visit (n = 416, see Figure 1). The multivariate model suggests that three parameters predict the likelihood of having an elevated BP measurement late in posttransplant follow-up (Table 2). First, age at transplant ≥5 years and <8 years confers a greater risk of elevated BP measurement (odds ratio 2.64) compared to patients aged ≤1 years at the time of transplant. Second, steroid exposure at the time of the last BP measurement increased the risk of elevated BP. Third, cGFR at last BP measurement also increased the risk of an elevated BP measurement: cGFR <90 mL/min/1.73 m2 conferred a threefold increase (odds ration 3.04) in the likelihood of an elevated BP measurement between 5 and 10 years following LT. Finally, time from transplant, measured as a continuous variable, did not reach significance in this model. There were no ethnic differences in the risk of elevated BP in the multivariate model. Owing to the apparent increased susceptibility of 5- to 7-year-olds to develop elevated BP, we looked for incidence of renal dysfunction or rejection in this age group: there was no significant difference in either of these complications compared with other age groups (Table S3). To analyze the relationship between renal dysfunction and elevated BP in greater detail, we examined whether low cGFR predicted elevated BP or whether elevated BP might be a harbinger of cGFR decline between 5 and 10 years post-LT. Based on the small numbers available, the Chi-square analysis data suggests that in this series, elevated BP may precede the onset of renal dysfunction (cGFR 8 μg/L or cyclosporine (CsA) trough levels >200 μg/L or number of visits with tacrolimus trough levels >5 μg/L or CsA trough levels >150 μg/L. We did not observe an effect of CNI exposure on BP status 5 to 10 years post-LT using this approach (Table S5). We also considered BP status according to number of years of CNI use. There was no observed effect of number of CNI years on BP status. CNI exposure and time since transplant were collinear (data not shown). Steroids are also commonly accepted to be major contributors to drug-induced hypertension. Steroid use at the time of BP measurement was a positive predictor of elevated BP both in our univariate and multivariate models. As such, we undertook a post hoc analysis to examine relative and cumulative steroid exposure, within the confines of the SPLIT database. First, we first examined whether prednisone use in the first 2 years following LT might predict long-term BP status, but no association was observed (p = 0.117). Next, as a surrogate for cumulative steroid exposure, we analyzed whether two successive visits with recorded steroid use increased the risk of elevated BP compared to a single visit: indeed, there was 2.8-fold greater risk of measuring an elevated BP with prolonged steroid exposure (Table S5). This study demonstrates that elevated BP measurements exist in as many as 27.5% of pediatric LT patients aged 5 years or more and at least 5 years post-LT. It shows a protective effect of younger age at transplant <1 year, the deleterious effect of steroid use and an association with cGFR <90mL mL/min/1.73 m2. Increasing evidence suggests that pediatric hypertension contributes to the burden of adult cardiovascular disease and that hypertensive children are subject to end-organ damage (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). Therefore, this analysis should offer incentive to community pediatricians as well as subspecialists following these patients in a tertiary-care setting to evaluate BP and other cardiovascular risk factors rigorously. According to our data, children who are transplanted before the age of 1 year seem to be spared from the risk of long-term BP elevation as compared to those transplanted in early childhood. We might have predicted this finding based on studies suggesting that younger patients have a lower incidence of CNI-induced hypertension than older 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 Scholar), except for the fact that children transplanted after the age of 8 may do better than their peers transplanted between the ages of 5 and 7, a result which speaks against a linear effect of age. In this series, the role of age at transplant in the susceptibility to develop elevated BP is unclear. Indeed, the age group ≤4 years is mostly comprised of infants less than 1 year of age who are transplanted early in life for biliary atresia and who have been shown to be less susceptible 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 univariate analysis confirmed these findings since age < 1 year at LT negatively predicted the risk of having an elevated BP measurement later in life. Thus, we propose that the seeming difference between the 5 and 7 year age group and the others may be an artifact because patient distribution is very uneven between age groups (Table S6). Rather, we conclude that the unique subset of infants transplanted in their first year of life may be protected from long-term posttransplant elevated BP. On the other hand, the effect of steroid use on long-term BP elevation is much more likely to be real. Indeed, hypertension is accepted to be a common side-effect of glucocorticoid use regardless of underlying disease or comorbidities. Thus, in practice, any BP assessment or intervention in the group of patients on short-term steroids is often postponed until the end of the steroid course. However, because the prolonged use of steroids as recorded at 2 or more successive visits confers an increased risk of long-term BP abnormalities, it may be advisable to confirm hypertension by conventional methods in patients requiring long-term steroids for indications such as rejection or posttransplant allo-immune hepatitis. Indeed, in these patients, treatment could help protect against long-term renal dysfunction (22System URD USRDS 2004; Annual Data Report. 2004.Google Scholar,28Staples A Wong C Risk factors for progression of chronic kidney disease.Curr Opin Pediatr. 2010; 22: 161-169Crossref PubMed Scopus (50) Google Scholar). The development of steroid-free protocols for the treatment of posttransplant complications is another important goal in the management of these patients. Interestingly, time since transplant did not reach statistical significance in the multivariate model, even if there appears to be a trend in that direction (Figure 1). It is unclear whether this is owing to sample size (n = 105 at 10 years) or whether duration of exposure to CNIs and other agents causing BP elevation is less of a problem than might be predicted. Remarkably, the surrogate measures for cumulative CNI exposure used in this report were not associated with an increased risk of elevated BP long-term post-LT. Perhaps, instead of cumulative exposure, the greater factor is individual susceptibility. On that note, ethnicity did not seem to predispose to elevated BP measurements in this cohort. Hypertension contributes to rapid decline of GFR in adults and children with or without a history of solid organ transplantation (22System URD USRDS 2004; Annual Data Report. 2004.Google Scholar,28Staples A Wong C Risk factors for progression of chronic kidney disease.Curr Opin Pediatr. 2010; 22: 161-169Crossref PubMed Scopus (50) Google Scholar, 29Locatelli F Marcelli D Comelli M et al.Proteinuria and blood pressure as causal components of progression to end-stage renal failure. Northern italian cooperative study group.Nephrol Dial Transplant. 1996; 11: 461-467Crossref PubMed Google Scholar, 30Klag MJ Whelton PK Randall BL et al.Blood pressure and end-stage renal disease in men.N Engl J Med. 1996; 334: 13-28Crossref PubMed Scopus (1439) Google Scholar, 31Mitsnefes M Ho PL McEnery PT Hypertension and progression of chronic renal insufficiency in children: A report of the north american pediatric renal transplant cooperative study (NAPRTCS).J Am Soc Nephrol. 2003; 14: 2618-2622Crossref PubMed Scopus (146) Google Scholar, 32Wingen AM Fabian-Bach C Schaefer F Mehis O Randomised multicentre study of a low-protein diet on the progression of chronic renal failure in children. European study group of nutritional treatment of chronic renal failure in childhood.Lancet. 1997; 349: 1117-1123Abstract Full Text Full Text PDF PubMed Scopus (235) Google Scholar). In 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). In our cohort, cGFR 95th percentile) for treatment to protect from renal comorbidities (23The fourth report on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents.Pediatrics. 2004; 114 (4th Report:): 555-576PubMed Google Scholar,33Portman RJ McNiece KL Swinford RD Braun MC Samuels JA Pediatric hypertension: Diagnosis, evaluation, management, and treatment for the primary care physician.Curr Probl Pediatr Adolesc Health Care. 2005; 35: 262-294Crossref PubMed Scopus (25) Google Scholar, 34Simonetti GD, Rizzi M, Bianchetti MG. Simple references for managing arterial hypertension in children with kidney disease. J Hypertens 28: 1109 [author reply 1109–10].Google Scholar, 35Lurbe E Cifkova R Cruickshank JK et al.Management of high blood pressure in children and adolescents: Recommendations of the european society of hypertension.J Hypertens. 2009; 27: 1719-1742Crossref PubMed Scopus (582) Google Scholar, 36Wuhl E Trivelli A Picca S et al.Strict blood-pressure control and progression of renal failure in children.N Engl J Med. 2009; 361: 1639-1650Crossref PubMed Scopus (654) Google Scholar). Although unpublished, this approach is being used by a growing number of centers. Although this study is the first to look at the long-term prevalence and predictive factors of elevated BP following pediatric liver transplantation, it has several limitations. First, it estimates the prevalence or risk factors of having elevated BP measurements at annual follow up visits rather than hypertension per se. Indeed, most centers recorded only one BP measurement per visit using an automated method rather than repeat-measures, but recent pediatric studies suggest that this is a commonly used approach (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,25Rodriguez BL Liese DD Fujimoto AD et al.Imperatore G, for the SEARCH study group Prevalence and correlates of elevated blood pressure in youth with diabetes mellitus: The search for diabetes in youth study.J Pediatr. 2010; 157: 245-251Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar). To be able to obtain a true estimate of hypertension, manual BP measurements at serial visits no more than 1 week apart should have been obtained and recorded to determine whether the patients truly had hypertension warranting further evaluation and treatment (23The fourth report on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents.Pediatrics. 2004; 114 (4th Report:): 555-576PubMed Google Scholar). Because this approach is quite labor intensive, having pointers or predictive factors that orient the clinician as to which patient to work up should prove a useful tool in the management of these patients. Of course, a significant fraction of patients with a single elevated BP measurement will normalize thereafter, as was observed in this study, confirming the need for a rigorous approach to identify true hypertension. Second, the BP arm of the SPLIT registry only included children 5 years of age or more at the time of BP measurement. Therefore, we were unable to assess with any certainty how factors during the first year impacted BP prior to age 5 in children transplanted as infants. In particular, Because children younger than 5 years of age at an anniversary visit were excluded from the BP study, we are unable to comment whether early posttransplant elevated BP might predict long-term risk of elevated BP, something which needs investigation. However, it is reassuring to find that steroid use in the first 2 years following LT did not put patients at increased risk of long-term elevated BP. In conclusion, it appears that as many as 20% of long-term pediatric liver transplant recipients may present with elevated BP measurements using standard automated techniques at an outpatient visit 5 to 10 years post-LT. Of these patients, as many as 15% may already be receiving treatment. Although single, automated measurements probably overestimate the prevalence of elevated BP, it is clearly a more frequent occurrence in pediatric LT recipients than a pediatric population of all-comers in which the prevalence of hypertension has been estimated to be 4% (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,25Rodriguez BL Liese DD Fujimoto AD et al.Imperatore G, for the SEARCH study group Prevalence and correlates of elevated blood pressure in youth with diabetes mellitus: The search for diabetes in youth study.J Pediatr. 2010; 157: 245-251Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar). Among those that present with an elevated BP measurement at one visit, as many as 62.5% will have another elevated BP measurement within a 5-year time frame. In light of the well-known risk of CNI-induced hypertension and associated renal disease in both children and adults, these patients warrant careful work-up and follow-up. To this end, we propose the algorithm in Figure 3. Hypertension is a common cause of morbidity and mortality in the adult population following liver transplantation. Now that pediatric LT patients survive well into adulthood and that the susceptibility of children to hypertensive complications is being increasingly recognized, managing the long-term and systemic complications of transplant is becoming the pediatrician’s responsibility. Therefore, transplant physicians and community pediatricians should work together to carefully monitor for the development of comorbidities such as hypertension and renal dysfunction and refer patients to the appropriate specialists when indicated. Identifying and treating hypertension early may prevent longer term morbidity and help hold the promise of normal life expectancy following solid organ transplant. This project was supported by grant number U01 DK061693 of the National Institute of Diabetes and Digestive and Kidney Diseases. The authors thank all the participating SPLIT centers. The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation. Additional Supporting Information may be found in the online version of this article: Download .doc (.26 MB) Help with doc files Table S1: Primary diagnosis and rejection episodes by age at transplantTable S2: Distribution of risk factors by BP status at last BP measurement and between 5 and 10 years posttransplantTable S3: Rejection episodes in the first 5 years and steroid use by age at transplantTable S4: cGFR at previous visit by last BP measurement and BP measurement at previous visit by cGFR at last BP visitTable S5: Univariate analysis of elevated BP 5 to 10 years posttransplantTable S6: Univariate analysis of immunosuppressant use and elevated BP 5 to 10 years posttransplant Please note: Wiley-Blackwell is not responsible for the content or functionality of any supporting materials supplied by the authors. Any queries (other than missing material) should be directed to the corresponding author for the article.