ORIGINAL ARTICLE: HEPATOLOGY
Biliary Atresia Is Associated With Hypertension
Robyn G. Matloff, yRebekah Diamond, yAlan Weinberg, zRonen Arnon, and zJeffrey M. Saland
ABSTRACT Objectives: The improved survival of pediatric liver transplant recipients is accompanied by an increase in long-term comorbidities. A recently highlighted concern, hypertension, is associated with chronic kidney disease (CKD) in this population and can result in other target-organ damage during childhood. The prevalence of hypertension in pediatric liver transplantation is imprecisely known. In addition, individual etiologies of liver failure may convey different risks of hypertension. We sought to study the effect of liver transplantation on the prevalence of hypertension and CKD in patients with biliary atresia (BA). Methods: We conducted a retrospective chart review of 160 patients with BA followed at the Mount Sinai Medical Center, New York, from 1987 to 2012. Data were accumulated from the initial and subsequent visits at approximately 6 months, 1, 3, 5, 10, and 15 years of age. Hypertension was defined as systolic blood pressure >95th percentile for age, sex, height, and/or use of antihypertensive medication. Renal function was examined over time. Data were stratified by liver transplantation status at the time of visit. Results: A high prevalence of hypertension was observed from the initial visit through age 10, independent of transplant status (transplanted: 48% initial visit and 13% after 10 years vs nontransplanted: 55% initial visit and 17% after 10 years [P ¼ ns for transplant status]). Mean estimated glomerular filtration rate (eGFR) was lower among liver transplant patients as compared with nontransplant patients and declined posttransplant. The incidence of CKD was higher among transplant patients. Conclusions: Hypertension is common among children with BA, independent of liver transplant status. Transplant patients had significantly reduced renal function, which continued to decline over time. Hypertension was not associated with reduced eGFR. Key Words: biliary atresia, chronic kidney disease, hypertension, liver transplantation
(JPGN 2015;61: 182–186)
Received July 8, 2014; accepted January 27, 2015. From the Division of Pediatric Nephrology, Maria Fareri Children’s Hospital of Westchester Medical Center, New York Medical College, Valhalla, the yDepartment of Health Evidence and Policy, and the zRecanati/Miller Transplantation Institute, New York, NY. Address correspondence and reprint requests to Robyn G. Matloff, MD, MPH, Division of Pediatric Nephrology, Maria Fareri Children’s Hospital of Westchester Medical Center, New York Medical College, Skyline Office #1N-C12, 40 Sunshine Cottage Rd, Valhalla, NY 10595 (e-mail: [email protected]). Funding for this work was provided by Icahn School of Medicine at Mount Sinai, Medical Student Research Office. The authors report no conflicts of interest. Copyright # 2015 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition DOI: 10.1097/MPG.0000000000000749
What Is Known
Success of pediatric liver transplantation is limited by a high prevalence of CKD. Hypertension is a well-known risk factor for the development of CKD. Hypertension has recently been identified as a longterm comorbid condition following pediatric LT.
What Is New
Biliary atresia is inherently associated with HTN. Hypertension may be preexisting before transplantation, and transplantation is not the sole etiology of HTN in patients with BA. Identification and management of HTN reflects a potentially modifiable risk factor for the development of chronic kidney and cardiovascular disease in patients with BA and pediatric LT in general.
T
he lifespan of recipients undergoing pediatric liver transplant has improved over time. This improved survival is marked, however, by an increase in long-term comorbidities, with hypertension being a recently highlighted concern. Among adult liver transplant recipients, hypertensive cardiovascular disease and renal failure are among the highest contributors to mortality (1). Although the exact prevalence of hypertension and the potential cardiovascular risk attributed to it in pediatric liver transplant patients remains unknown, the fact that hypertension is an independent risk factor for chronic kidney disease (CKD) in this population makes its negative impact clear enough (2,3). Childhood hypertension tends to persist (‘‘track’’) to adulthood, and end-organ hypertensive damage begins to manifest during childhood (2). Thus, there is a reason to believe that early recognition and treatment of hypertension in children with liver transplants is likely to be beneficial. The prevalence of hypertension in subjects enrolled in the Survivors of Pediatric Liver Transplantation (SPLIT) registry, a registry of 815 subjects, varied between 17.5% and 27.5% when measured 5 to 10 years after transplant. Age at transplant, decreased glomerular filtration rate (GFR), and recent steroid use were independent risk factors for elevated blood pressure (3). We performed a single-center chart review to determine the exact prevalence and evolution of hypertension in pediatric liver transplant recipients. We chose to investigate a group with a single underlying disease, biliary atresia (BA), to reduce confounding variables and allow for a more uniform assessment of the effect of liver transplantation and other clinical factors on blood pressure and diagnosis of hypertension. We hypothesized that children would demonstrate a significant transition from nonhypertensive to hypertensive related to receiving a liver transplant.
182 JPGN Volume 61, Number 2, August 2015 Copyright 2015 by ESPGHAN and NASPGHAN. Unauthorized reproduction of this article is prohibited.
JPGN
Volume 61, Number 2, August 2015
Biliary Atresia Is Associated With Hypertension
METHODS We conducted a retrospective chart review of 160 patients with BA followed by the Division of Pediatric Hepatology at the Mount Sinai Medical Center from January 1987 to May 2012. Data were recorded from the initial visit and from visits at approximately 1, 3, 5, 10, and 15 years of age, whenever available. Because nearly all of the patients were diagnosed in early infancy, the age at each visit was roughly equivalent to the years since diagnosis. A patient’s transplant status was determined at each visit, as a state function, not set by the ultimate transplant status. For example, a patient could be analyzed as ‘‘nontransplanted’’ at ages 1 and 3 years, and after transplant at age 4 years, as ‘‘transplanted’’ for the following visits. Because our interest was in chronic hypertension rather than acute posttransplant effects, we did not include data from any visit fewer than 6 months after transplant. Hypertension was defined as systolic blood pressure >95th percentile based on age, sex, height, and/or use of antihypertensive medication (2). Systolic blood pressure index was defined as the patient’s blood pressure divided by the systolic blood pressure corresponding to the 95th percentile for sex and height. Data were stratified by liver transplantation status at the time of visit. GFR was calculated through the modified Schwartz equation (4): 0:41 heightðcmÞ serum are atinineðmg=dLÞ Statistical analysis was performed using SAS version 9.2 (SAS Institute, Inc, Cary, NC). Group comparisons were made using x2 analysis and Student t test. Dichotomous outcomes such as hypertension were analyzed using generalized estimating equation methodology to analyze repeated measures over time. Because repeated measurements, such as blood pressure, within patients may be correlated, this procedure allows one to model ‘‘correlation structure’’ or covariance pattern. Continuous measurements such as estimated GFR (eGFR) and SBP index were modeled using the PROC MIXED procedure in SAS, which is similar to an analysis of variance procedure for repeated measurements. Significance was set a P < 0.05 for a significant measure over time as consistent with Akaike information criterion, allowing one to discern the best fit for a covariance pattern (5).
RESULTS A total of 159 patients were included in the analysis. The remaining patients were excluded secondary to insufficient data. Characteristics of our study population are found in Table 1. One hundred and twelve patients (75%) underwent liver transplantation. Both the transplanted and the nontransplanted groups were predominantly female (59% and 60%, respectively), and all of the TABLE 1. Study cohort characteristics Liver transplant not required during study period (N ¼ 37) Sex Age at liver transplant, mo (percentile) Follow-up, y
Male 15 (41%) Female 22 (59%) Median (25th–75th) N/A 1.5 (1–5)
N/A ¼ not applicable; ns ¼ not significant.
www.jpgn.org
Liver transplant required during study period (N ¼ 112)
P
Male 45 (40%) ns Female 67 (60%) Median N/A (25th–75th) 11 (9,24) 6.9 (3.5–11)
Biliary Atresia Is Associated With Hypertension
Robyn G. Matloff, yRebekah Diamond, yAlan Weinberg, zRonen Arnon, and zJeffrey M. Saland
ABSTRACT Objectives: The improved survival of pediatric liver transplant recipients is accompanied by an increase in long-term comorbidities. A recently highlighted concern, hypertension, is associated with chronic kidney disease (CKD) in this population and can result in other target-organ damage during childhood. The prevalence of hypertension in pediatric liver transplantation is imprecisely known. In addition, individual etiologies of liver failure may convey different risks of hypertension. We sought to study the effect of liver transplantation on the prevalence of hypertension and CKD in patients with biliary atresia (BA). Methods: We conducted a retrospective chart review of 160 patients with BA followed at the Mount Sinai Medical Center, New York, from 1987 to 2012. Data were accumulated from the initial and subsequent visits at approximately 6 months, 1, 3, 5, 10, and 15 years of age. Hypertension was defined as systolic blood pressure >95th percentile for age, sex, height, and/or use of antihypertensive medication. Renal function was examined over time. Data were stratified by liver transplantation status at the time of visit. Results: A high prevalence of hypertension was observed from the initial visit through age 10, independent of transplant status (transplanted: 48% initial visit and 13% after 10 years vs nontransplanted: 55% initial visit and 17% after 10 years [P ¼ ns for transplant status]). Mean estimated glomerular filtration rate (eGFR) was lower among liver transplant patients as compared with nontransplant patients and declined posttransplant. The incidence of CKD was higher among transplant patients. Conclusions: Hypertension is common among children with BA, independent of liver transplant status. Transplant patients had significantly reduced renal function, which continued to decline over time. Hypertension was not associated with reduced eGFR. Key Words: biliary atresia, chronic kidney disease, hypertension, liver transplantation
(JPGN 2015;61: 182–186)
Received July 8, 2014; accepted January 27, 2015. From the Division of Pediatric Nephrology, Maria Fareri Children’s Hospital of Westchester Medical Center, New York Medical College, Valhalla, the yDepartment of Health Evidence and Policy, and the zRecanati/Miller Transplantation Institute, New York, NY. Address correspondence and reprint requests to Robyn G. Matloff, MD, MPH, Division of Pediatric Nephrology, Maria Fareri Children’s Hospital of Westchester Medical Center, New York Medical College, Skyline Office #1N-C12, 40 Sunshine Cottage Rd, Valhalla, NY 10595 (e-mail: [email protected]). Funding for this work was provided by Icahn School of Medicine at Mount Sinai, Medical Student Research Office. The authors report no conflicts of interest. Copyright # 2015 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition DOI: 10.1097/MPG.0000000000000749
What Is Known
Success of pediatric liver transplantation is limited by a high prevalence of CKD. Hypertension is a well-known risk factor for the development of CKD. Hypertension has recently been identified as a longterm comorbid condition following pediatric LT.
What Is New
Biliary atresia is inherently associated with HTN. Hypertension may be preexisting before transplantation, and transplantation is not the sole etiology of HTN in patients with BA. Identification and management of HTN reflects a potentially modifiable risk factor for the development of chronic kidney and cardiovascular disease in patients with BA and pediatric LT in general.
T
he lifespan of recipients undergoing pediatric liver transplant has improved over time. This improved survival is marked, however, by an increase in long-term comorbidities, with hypertension being a recently highlighted concern. Among adult liver transplant recipients, hypertensive cardiovascular disease and renal failure are among the highest contributors to mortality (1). Although the exact prevalence of hypertension and the potential cardiovascular risk attributed to it in pediatric liver transplant patients remains unknown, the fact that hypertension is an independent risk factor for chronic kidney disease (CKD) in this population makes its negative impact clear enough (2,3). Childhood hypertension tends to persist (‘‘track’’) to adulthood, and end-organ hypertensive damage begins to manifest during childhood (2). Thus, there is a reason to believe that early recognition and treatment of hypertension in children with liver transplants is likely to be beneficial. The prevalence of hypertension in subjects enrolled in the Survivors of Pediatric Liver Transplantation (SPLIT) registry, a registry of 815 subjects, varied between 17.5% and 27.5% when measured 5 to 10 years after transplant. Age at transplant, decreased glomerular filtration rate (GFR), and recent steroid use were independent risk factors for elevated blood pressure (3). We performed a single-center chart review to determine the exact prevalence and evolution of hypertension in pediatric liver transplant recipients. We chose to investigate a group with a single underlying disease, biliary atresia (BA), to reduce confounding variables and allow for a more uniform assessment of the effect of liver transplantation and other clinical factors on blood pressure and diagnosis of hypertension. We hypothesized that children would demonstrate a significant transition from nonhypertensive to hypertensive related to receiving a liver transplant.
182 JPGN Volume 61, Number 2, August 2015 Copyright 2015 by ESPGHAN and NASPGHAN. Unauthorized reproduction of this article is prohibited.
JPGN
Volume 61, Number 2, August 2015
Biliary Atresia Is Associated With Hypertension
METHODS We conducted a retrospective chart review of 160 patients with BA followed by the Division of Pediatric Hepatology at the Mount Sinai Medical Center from January 1987 to May 2012. Data were recorded from the initial visit and from visits at approximately 1, 3, 5, 10, and 15 years of age, whenever available. Because nearly all of the patients were diagnosed in early infancy, the age at each visit was roughly equivalent to the years since diagnosis. A patient’s transplant status was determined at each visit, as a state function, not set by the ultimate transplant status. For example, a patient could be analyzed as ‘‘nontransplanted’’ at ages 1 and 3 years, and after transplant at age 4 years, as ‘‘transplanted’’ for the following visits. Because our interest was in chronic hypertension rather than acute posttransplant effects, we did not include data from any visit fewer than 6 months after transplant. Hypertension was defined as systolic blood pressure >95th percentile based on age, sex, height, and/or use of antihypertensive medication (2). Systolic blood pressure index was defined as the patient’s blood pressure divided by the systolic blood pressure corresponding to the 95th percentile for sex and height. Data were stratified by liver transplantation status at the time of visit. GFR was calculated through the modified Schwartz equation (4): 0:41 heightðcmÞ serum are atinineðmg=dLÞ Statistical analysis was performed using SAS version 9.2 (SAS Institute, Inc, Cary, NC). Group comparisons were made using x2 analysis and Student t test. Dichotomous outcomes such as hypertension were analyzed using generalized estimating equation methodology to analyze repeated measures over time. Because repeated measurements, such as blood pressure, within patients may be correlated, this procedure allows one to model ‘‘correlation structure’’ or covariance pattern. Continuous measurements such as estimated GFR (eGFR) and SBP index were modeled using the PROC MIXED procedure in SAS, which is similar to an analysis of variance procedure for repeated measurements. Significance was set a P < 0.05 for a significant measure over time as consistent with Akaike information criterion, allowing one to discern the best fit for a covariance pattern (5).
RESULTS A total of 159 patients were included in the analysis. The remaining patients were excluded secondary to insufficient data. Characteristics of our study population are found in Table 1. One hundred and twelve patients (75%) underwent liver transplantation. Both the transplanted and the nontransplanted groups were predominantly female (59% and 60%, respectively), and all of the TABLE 1. Study cohort characteristics Liver transplant not required during study period (N ¼ 37) Sex Age at liver transplant, mo (percentile) Follow-up, y
Male 15 (41%) Female 22 (59%) Median (25th–75th) N/A 1.5 (1–5)
N/A ¼ not applicable; ns ¼ not significant.
www.jpgn.org
Liver transplant required during study period (N ¼ 112)
P
Male 45 (40%) ns Female 67 (60%) Median N/A (25th–75th) 11 (9,24) 6.9 (3.5–11)
