Demographics of blood pressure and hypertension in children on renal replacement therapy in Europe
2011; Elsevier BV; Volume: 80; Issue: 10 Linguagem: Inglês
10.1038/ki.2011.232
ISSN1523-1755
AutoresAnne Marijn Kramer, Karlijn J. van Stralen, Kitty J. Jager, Franz Schaefer, Enrico Verrina, Tomáš Seeman, Malcolm Lewis, Michael Böehm, Giacomo D. Simonetti, Gregor Novljan, Jaap W. Groothoff,
Tópico(s)Renal and Vascular Pathologies
ResumoHypertension is a well-known complication in children on renal replacement therapy and an important risk factor for cardiovascular disease in later life. In order to define the prevalence of and risk factors for hypertension among children, we enrolled 3337 pediatric patients from 15 countries in the ESPN/ERA-EDTA Registry of whom 464 were on hemodialysis, 851 on peritoneal dialysis, and 2023 had received a renal allograft. Hypertension was defined as either systolic or diastolic blood pressures in the 95th percentile or greater for age, height, and gender or use of antihypertensive medication. Analyses were adjusted for age, gender, duration, and modality of renal replacement therapy. In 10 countries in which information on the use of antihypertensive medication was available, hypertension was present in over two-thirds of hemodialysis, peritoneal dialysis, or transplant patients. Blood pressure values above the 95th percentile were significantly more prevalent in very young patients (under 3 years) compared to 13- to 17-year olds (odds ratio 2.47), during the first year compared to over 5 years of renal replacement therapy (odds ratio 1.80), and in patients on hemodialysis compared to transplant recipients or those on peritoneal dialysis (odds ratios of 2.48 and 1.59, respectively). Over time, mean blood pressures decreased in both hemodialysis and transplant patients, but not in peritoneal dialysis patients. Hence, our findings highlight the extent of the problem of hypertension in children with end-stage renal disease in Europe. Hypertension is a well-known complication in children on renal replacement therapy and an important risk factor for cardiovascular disease in later life. In order to define the prevalence of and risk factors for hypertension among children, we enrolled 3337 pediatric patients from 15 countries in the ESPN/ERA-EDTA Registry of whom 464 were on hemodialysis, 851 on peritoneal dialysis, and 2023 had received a renal allograft. Hypertension was defined as either systolic or diastolic blood pressures in the 95th percentile or greater for age, height, and gender or use of antihypertensive medication. Analyses were adjusted for age, gender, duration, and modality of renal replacement therapy. In 10 countries in which information on the use of antihypertensive medication was available, hypertension was present in over two-thirds of hemodialysis, peritoneal dialysis, or transplant patients. Blood pressure values above the 95th percentile were significantly more prevalent in very young patients (under 3 years) compared to 13- to 17-year olds (odds ratio 2.47), during the first year compared to over 5 years of renal replacement therapy (odds ratio 1.80), and in patients on hemodialysis compared to transplant recipients or those on peritoneal dialysis (odds ratios of 2.48 and 1.59, respectively). Over time, mean blood pressures decreased in both hemodialysis and transplant patients, but not in peritoneal dialysis patients. Hence, our findings highlight the extent of the problem of hypertension in children with end-stage renal disease in Europe. Hypertension is a frequently reported complication in children with end-stage renal disease, with its prevalence varying from 48 to 79% depending on the exact definition of hypertension.1.Chavers B.M. Solid C.A. Daniels F.X. et al.Hypertension in pediatric long-term hemodialysis patients in the United States.Clin J Am Soc Nephrol. 2009; 4: 1363-1369Crossref PubMed Scopus (51) Google Scholar, 2.Seeman T. Hypertension after renal transplantation.Pediatr Nephrol. 2009; 24: 959-972Crossref PubMed Scopus (49) Google Scholar, 3.Tkaczyk M. Nowicki M. Balasz-Chmielewska I. et al.Hypertension in dialysed children: the prevalence and therapeutic approach in Poland—a nationwide survey.Nephrol Dial Transplant. 2006; 21: 736-742Crossref PubMed Scopus (41) Google Scholar In contrast to numerous studies on hypertension and end-stage renal disease in adults,4.Agarwal R. Nissenson A.R. Batlle D. et al.Prevalence, treatment, and control of hypertension in chronic hemodialysis patients in the United States.Am J Med. 2003; 115: 291-297Abstract Full Text Full Text PDF PubMed Scopus (353) Google Scholar little has been reported on the prevalence and treatment of hypertension in the pediatric renal replacement therapy (RRT) population in Europe. Furthermore, existing information is usually limited to hemodialysis (HD) and peritoneal dialysis (PD) patients, whereas information on transplanted patients is scarce and comes from single-centre experiences.5.Seeman T. Simkova E. Kreisinger J. et al.Control of hypertension in children after renal transplantation.Pediatr Transplant. 2006; 10: 316-322Crossref PubMed Scopus (52) Google Scholar The registry of the European Society for Pediatric Nephrology and the European Renal Association and European Dialysis and Transplant Association (the ESPN/ERA-EDTA Registry) aims to increase the amount and quality of information on children and adolescents on RRT in Europe.6.Tizard E.J. Verrina E. van Stralen K.J. et al.Progress with the European Society for Paediatric Nephrology (ESPN)/ERA-EDTA Registry for children with established renal failure (ERF).Nephrol Dial Transplant. 2009; 24: 2615-2617Crossref PubMed Scopus (29) Google Scholar We therefore aimed to determine (1) the distribution of blood pressure and prevalence of high blood pressure and hypertension in the European pediatric RRT population, (2) the risk factors for high blood pressure, (3) factors associated with the use of antihypertensive medication, (4) the evolution of blood pressure over time, and, finally, (5) the relationship between blood pressure and body mass index (BMI). Between 01 January 1999 and 01 January 2010, physicians of 15 countries provided data on 3785 children on RRT to the ESPN/ERA-EDTA registry. We obtained data on 13,267 blood pressure measurements from 3337 patients, a median of three measurements with a range of 1 to 22 per patient. Mean age at the initiation of RRT was 11 years and 60.3% were male. Congenital anomalies of the kidney and urinary tract were the most frequent underlying disorder. Most children (55.7%) received PD as their initial treatment modality, whereas 11% started with a pre-emptive transplantation. At the time of the blood pressure measurement, 60.6% had a functional renal graft, whereas 25.5% were on PD and 13.9% on HD (Table 1). Of all children, 30% started RRT before the age of 4 years, whereas 21.7% had started RRT when they were over 13 years of age.Table 1Demographic and clinical characteristics populationVariablesAll (n=3337)Sex Male2015 (60.3) Female1322 (39.7)Age at time of measurement, years 0–3388 (11.6) 4–121201 (36.0) 13–171748 (52.4)Primary renal disease (112 missing) Glomerulonephritis/sclerosis451 (13.5) CAKUT and pyelonephritis1412 (42.3) Cystic kidneys339 (10.2) Hereditary nephropathy280 (8.4) Ischemic renal failure72 (2.2) Hemolytic uremic syndrome129 (3.9) Metabolic disorder107 (3.2) Vasculitis65 (1.9) Miscellaneous162 (4.9) Unknown/missing320 (9.9)Time on RRT at time of measurement, years (166 missing) 0–0.99329 (10.4) 1–2.991092 (34.4) 3–4.99627 (19.8) >51123 (35.4)Treatment modality at time of measurement HD464 (13.9) PD851 (25.5) Tx2023 (60.6)Body mass index <5 percentile236 (8.8) 20–84 percentile1642 (61.2) ≥85 percentile807 (30.1)Abbreviations: CAKUT, congenital anomalies of the kidney and urinary tract; HD, hemodialysis; PD, peritoneal dialysis; RRT, renal replacement therapy; Tx, transplant.Data presented as n(%). Open table in a new tab Abbreviations: CAKUT, congenital anomalies of the kidney and urinary tract; HD, hemodialysis; PD, peritoneal dialysis; RRT, renal replacement therapy; Tx, transplant. Data presented as n(%). The standard deviation scores (SDSs) of systolic blood pressure by treatment modality and age groups showed a higher SDS in the patients on HD (Figure 1). Mean absolute blood pressure values are presented in Supplementary Appendix S2. Uncontrolled hypertension, defined as a systolic or diastolic blood pressure SDS ≥95th percentile irrespective of the use of medication, was present in 45.5% of the HD, 35.5% of the PD, and 21.4% of the transplanted patients during the course of the study (Figure 2). Download .doc (.04 MB) Help with doc files Supplementary Appendix 1 and 2Figure 2Distribution of blood pressure percentiles in different subgroups of patients.View Large Image Figure ViewerDownload (PPT) Data were available from 10 countries concerning the use of antihypertensive medication. In these countries, 51.9% of all patients were using antihypertensive medication (interquartile range 49.3–65.7%). Hypertension, defined as systolic or diastolic blood pressure ≥95th percentile or use of antihypertensive medication, was present in 69.7% of HD, 68.2% of PD, and 66.5% of transplanted patients. Of the patients treated with antihypertensive medication, 63.8% of HD patients, 54.6% of PD patients, and 26.6% of transplanted patients had a blood pressure above the 95th percentile, leaving 26.2% of HD patients, 45.4% of PD patients, and 73.4% of transplant patients with controlled hypertension. Only 13.9% of HD, 24.9% of PD, and 24.9% of transplant patients had blood pressures below the 75th percentile. Among those not treated with antihypertensive medication, 19.8% of HD patients, 21.3% of PD patients, and 5.8% of transplant recipients had a blood pressure above the 95th percentile, whereas 47.6%, 52.3%, and 69.5% had blood pressures levels below the 75th percentile, respectively. Among countries from which data were available from 1999 through 2009, the prevalence of hypertension in Europe remained unchanged (56%). Younger age, a shorter duration of RRT, and being on dialysis were significantly associated with uncontrolled hypertension (systolic or diastolic blood pressure ≥95th percentile; Figure 3). Furthermore, patients with glomerulonephritis, hereditary nephropathy, vasculitis, or other known type of kidney disorders had a twofold increased risk of having uncontrolled hypertension as compared with patients with congenital anomalies of the kidney and urinary tract. Nearly, all factors had similar associations for diastolic and systolic blood pressure SDS (Table 2). Associations were generally stronger for systolic blood pressure SDS than for diastolic blood pressure SDS, because of the mean SDS being lower for diastolic than systolic blood pressures. As an exception, however, males had higher diastolic blood pressure SDS as compared with females, but had similar systolic blood pressure SDS.Table 2Factors associated with mean blood pressure SDSMean systolic blood pressure SDSMean diastolic blood pressure SDSTotal1.00 (0.92–1.07)0.76 (0.70–0.82)Age (years; adjusted for sex, treatment modality, time on RRT, primary renal disease) 0–31.38 (1.26–1.50)aSignificantly different from reference population.1.32 (1.22–1.42)aSignificantly different from reference population. 4–121.09 (1.03–1.15)aSignificantly different from reference population.0.78 (0.73–0.83)aSignificantly different from reference population. 13–180.84bReference group.0.63bReference group.Sex (adjusted for age, treatment modality, time on RRT, primary renal disease) Male0.99bReference group.0.79bReference group. Female1.00 (0.92–1.08)0.71 (0.65–0.78)aSignificantly different from reference population.Treatment modality (adjusted for age, sex, time on RRT, primary renal disease) HD1.51 (1.41–1.61)aSignificantly different from reference population.1.13 (1.05–1.21)aSignificantly different from reference population. PD0.97 (0.89–1.06)aSignificantly different from reference population.0.86 (0.79–0.93)aSignificantly different from reference population. Tx0.89bReference group.0.63bReference group.Time on RRT (years; adjusted for age, sex, treatment modality, primary renal disease) 0–0.991.28 (1.16–1.40)aSignificantly different from reference population.0.99 (0.90–1.09)aSignificantly different from reference population. 1–2.991.04 (0.96–1.11)aSignificantly different from reference population.0.79 (0.72–0.85)aSignificantly different from reference population. 3–4.990.96 (0.89–1.03)0.75 (0.69–0.81) ≥50.90bReference group.0.69Primary renal disease (adjusted for age, sex, treatment modality, time on RRT) CAKUT and pyelonephritis0.79bReference group.0.63bReference group. Glomerulonephritis/sclerosis1.21 (1.09–1.33)aSignificantly different from reference population.0.99 (0.90–1.08)aSignificantly different from reference population. Cystic kidneys1.11 (0.98–1.25)0.80 (0.70–0.91)aSignificantly different from reference population. Hereditary nephropathy1.19 (1.03–1.35)aSignificantly different from reference population.0.83 (0.72–0.93)aSignificantly different from reference population. Ischemic renal failure0.97 (0.71–1.22)0.64 (0.44–0.82) Hemolytic uremic syndrome1.14 (0.94–1.33)aSignificantly different from reference population.0.88 (0.73–1.03)aSignificantly different from reference population. Metabolic disorder1.05 (0.82–1.33)aSignificantly different from reference population.0.78 (0.61–0.96) Vasculitis1.45 (1.15–1.74)aSignificantly different from reference population.1.04 (0.81–1.27)aSignificantly different from reference population. Miscellaneous1.16 (0.99–1.34)aSignificantly different from reference population.0.93 (0.79–1.07)aSignificantly different from reference population. Unknown/missing1.06 (0.87–1.25)aSignificantly different from reference population.0.76 (0.60–0.92)Abbreviations: CAKUT, congenital anomalies of the kidney and urinary tract; HD, hemodialysis; PD, peritoneal dialysis; RRT, renal replacement therapy; SDS, standard deviation scores; Tx, transplant.a Significantly different from reference population.b Reference group. Open table in a new tab Abbreviations: CAKUT, congenital anomalies of the kidney and urinary tract; HD, hemodialysis; PD, peritoneal dialysis; RRT, renal replacement therapy; SDS, standard deviation scores; Tx, transplant. Patients on HD (58.2%) and PD (52.0%) received antihypertensive medication more frequently as compared with transplanted patients (50.0%). Younger patients receiving PD (42.3% in the youngest age group) or who had been transplanted (28.0%) were less often treated with antihypertensive medication compared with older patients (P<0.05). Furthermore, as compared with patients with congenital anomalies of the kidney and urinary tract, in whom 42.0% used antihypertensive medication, patients with vasculitis (84.0%), hemolytic uremic syndrome (72.6%), and glomerulonephritis (69.0%) used antihypertensive medication significantly more often. All effects remained significant after adjustment for potential confounders. There were no differences in the use of antihypertensive medication between males and females, nor did we find an association with the duration of RRT. We compared the development in blood pressure SDS over time among children who had a blood pressure <95th percentile with those who had a blood pressure ≥95th percentile in the first 3 months after initiation of the treatment modality (Figure 4). In children commencing HD or receiving a transplant with a high blood pressure SDS, a statistically significant decline in systolic blood pressure SDS occurred in the first year after initiation of the respective treatment modality (first year SDS change=-1.3 on HD and -1.7 after transplantation (both P<0.05)). In the children with a non-elevated blood pressure at initiation of HD or transplant, blood pressures tended to increase over time. Among PD patients, blood pressure SDS did not change significantly over time, irrespective of having a low or high blood pressure at the start. In children on HD, a lower BMI was associated with a higher systolic and diastolic blood pressure SDS (Figure 5). Conversely, both diastolic and systolic blood pressure SDS of transplanted children were higher in children with a higher BMI (regression coefficient=0.07, P<0.01 per BMI category increase for systolic blood pressure SDS and regression coefficient=0.03, P<0.01 per BMI category increase for diastolic blood pressure SDS). We found a high prevalence of hypertension in European children on RRT. Very young patients had a significantly higher blood pressure SDS than older children. HD patients had the highest blood pressure SDS at onset of therapy, but over time blood pressure decreased, in contrast to PD patients in whom blood pressure did not change. In our dialysis patients, 54.4% had a blood pressure ≥95th percentile irrespective of medication use, which is in line with a US study from Mitsnefes et al.7.Mitsnefes M. Stablein D. Hypertension in pediatric patients on long-term dialysis: a report of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS).Am J Kidney Dis. 2005; 45: 309-315Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar who found 56.9% when using the same definition. However, when the use of antihypertensive medication was included in the definition of hypertension, the prevalence of hypertension was 69% in HD patients and 49.9% in transplant patients. This was much lower than US population, which showed prevalences of 79% among HD1.Chavers B.M. Solid C.A. Daniels F.X. et al.Hypertension in pediatric long-term hemodialysis patients in the United States.Clin J Am Soc Nephrol. 2009; 4: 1363-1369Crossref PubMed Scopus (51) Google Scholar and 58% among transplant patients,8.Sorof J.M. Sullivan E.K. Tejani A. et al.Antihypertensive medication and renal allograft failure: a North American Pediatric Renal Transplant Cooperative Study report.J Am Soc Nephrol. 1999; 10: 1324-1330PubMed Google Scholar which suggests a lower use of antihypertensive medication in Europe. Two other European studies showed varying results, finding 55% in Polish dialysis patients3.Tkaczyk M. Nowicki M. Balasz-Chmielewska I. et al.Hypertension in dialysed children: the prevalence and therapeutic approach in Poland—a nationwide survey.Nephrol Dial Transplant. 2006; 21: 736-742Crossref PubMed Scopus (41) Google Scholar and 89% in renal transplant recipients from the Czech Republic.5.Seeman T. Simkova E. Kreisinger J. et al.Control of hypertension in children after renal transplantation.Pediatr Transplant. 2006; 10: 316-322Crossref PubMed Scopus (52) Google Scholar Patients younger than 3 years of age had a significantly higher blood pressure SDS than adolescents. At the same time, these very young patients on PD had on average a lower use of antihypertensive drugs as compared with older children. Furthermore, even though very young children on HD had the most severe overall degree of hypertension, the use of antihypertensive medication was no different from other children on HD. Both findings suggest undertreatment of hypertension in these very young children. A general reluctance to prescribe antihypertensive medication in the absence of information about their safety and efficacy profiles in this age group might have contributed to these outcomes. There was a persistent hypertensive status in the PD population. This is in keeping with a US registry report.9.Mitsnefes M. Stablein D. Hypertension in pediatric patients on long-term dialysis: a report of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS).Am J Kidney Dis. 2005; 45: 309-315Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar Blood pressure in HD patients was highest at the onset of RRT in comparison to PD and transplant patients but decreased over time, in contrast to the PD group. However, HD patients with a blood pressure below the 95th percentile at initiation of HD showed an increase instead of a decrease of blood pressure over time. Both these trends in PD and HD patients demonstrate the difficulty of controlling blood pressure in the dialysis population. One possible explanation is the difficulty of estimating the dry body weight in a growing child on dialysis at the moment when residual diuresis is decreasing and, consequently, the chance of overhydration is increasing.10.Holtta T. Happonen J.M. Ronnholm K. et al.Hypertension, cardiac state, and the role of volume overload during peritoneal dialysis.Pediatr Nephrol. 2001; 16: 324-331Crossref PubMed Scopus (29) Google Scholar In transplant patients, the mean blood pressure strongly declined after transplantation, and was around 1SDS 1 year post transplantation, irrespective of whether the patients had high or low blood pressure initially. The findings in HD and transplant patients suggest a more adequate treatment of hypertension over time in these patients. However, certain limitations in this study challenge such definite conclusions at this point. For instance, the mean decrease in blood pressure in HD and transplant patients over time could also partly be explained by the phenomenon of regression to the mean, as there was selection based on a single high or low blood pressure measurement. Second, we could only analyze a limited number of patients for the follow-up of blood pressure over time and it is not certain if this sample is representative for the whole population. Incident patients with three blood pressure measurements during follow-up were included, of whom the first measurement had to take place within the first 3 months after initiation of RRT. We requested only one yearly follow-up measurement, and only a few incident patients were on a single treatment for three subsequent years. For example, if a patient underwent transplantation within 2 years after initiation of dialysis, he might not have had three reported measurements while being on dialysis. Nevertheless, this analysis might give an indication on what is happening on follow-up, especially among pediatric renal allograft recipients, as no other information is yet available on this group. We found remarkably high blood pressure SDS in children on HD with a low BMI. This is in accordance with data from the adult population, in which being underweight was associated with a higher prevalence of hypertension in HD patients.11.Salahudeen A.K. Fleischmann E.H. Bower J.D. et al.Underweight rather than overweight is associated with higher prevalence of hypertension: BP vs BMI in haemodialysis population.Nephrol Dial Transplant. 2004; 19: 427-432Crossref PubMed Scopus (22) Google Scholar Although we adjusted for age, sex, and primary renal disease, it seems plausible to assume that the children who were underweight on HD had more comorbidities as compared with underweight renal allograft recipients. In contrast, blood pressure distribution in the transplanted children was more reflective of findings in the general pediatric and adult population, showing a higher prevalence of hypertension in children with obesity.12.Flynn J.T. Pediatric hypertension update.Curr Opin Nephrol Hypertens. 2010; 19: 292-297Crossref PubMed Scopus (21) Google Scholar There were several limitations to our study, the first of which is that we did not know how blood pressure was measured at the participating centers. Failure to standardize blood pressure measurements across sites could have introduced errors in the blood pressure measurements. However, the error in measurements is most likely unrelated to the 'real' presence of hypertension and is almost certainly unrelated to the analyzed factors. Therefore, this misclassification will have mainly lead to dilution of the effects found, resulting in less significant associations between blood pressure SDS and other factors. More precise measurements would be expected with ambulatory blood pressure monitoring,13.Wuhl E. Hadtstein C. Mehls O. et al.Home, clinic, and ambulatory blood pressure monitoring in children with chronic renal failure.Pediatr Res. 2004; 55: 492-497Crossref PubMed Scopus (109) Google Scholar which has the capacity to reveal white coat hypertension and masked hypertension and shows a better correlation with target organ damage such as left ventricular hypertrophy. However, this study reflects clinical practice in most European countries, where office blood pressure measurement is still the mainstay of blood pressure management. Furthermore, as we found many statistically significant effects in our study, we believe that the effect of the error was limited. There was a lack of information with respect to the exact timing of blood pressure measurements. In general, we requested pre-dialysis blood pressure readings. Use of pre-dialysis blood pressure may overestimate blood pressure, possibly partly explaining the high prevalence of hypertension in the HD patients as compared with PD patients. However, Chavers et al.14.Chavers B.M. Solid C.A. Daniels F.X. et al.Hypertension in pediatric long-term hemodialysis patients in the United States.Clin J Am Soc Nephrol. 2009; 4: 1363-1369Crossref PubMed Scopus (24) Google Scholar found that pre- and post-HD blood pressures were highly correlated in children on HD and only in 8% of their population would re-categorization be needed from hypertensive to normotensive if based on post-dialysis instead of pre-dialysis blood pressure. In conclusion, we demonstrate that, although there is a lower percentage of hypertension in Europe than in the US, hypertension is still inadequately treated in a large proportion of European children receiving RRT, as 48.5% of the children had a blood pressure ≥95th percentile despite antihypertensive medication. Hence, our findings highlight the dimension of the problem of hypertension in children with end-stage renal disease both before and after transplantation. For this study, we used data derived from the ESPN/ERA-EDTA Registry, a large international registry collecting data via national pediatric registries from 31 European countries, which has been described previously.6.Tizard E.J. Verrina E. van Stralen K.J. et al.Progress with the European Society for Paediatric Nephrology (ESPN)/ERA-EDTA Registry for children with established renal failure (ERF).Nephrol Dial Transplant. 2009; 24: 2615-2617Crossref PubMed Scopus (29) Google Scholar,15.van Stralen K.J. Tizard E.J. Verrina E. et al.Demographics of paediatric renal replacement therapy in Europe: 2007 annual report of the ESPN/ERA-EDTA registry.Pediatr Nephrol. 2010; 25: 1379-1382Crossref PubMed Scopus (35) Google Scholar Demographic data obtained during clinical care included, among others, date of birth, sex, height, weight, primary renal disease, systolic and diastolic blood pressure, date of start RRT, use of antihypertensive medication, therapy history, and treatment modality at the time of measurement. We included patients whose data were available regarding their blood pressure or use of antihypertensive medication for the period from 1999 and onward. This included data from the following countries and periods: Belarus (2008), the Czech Republic (2007–2008), Estonia (2009), Finland (1999–2008), Italy (1999–2009, dialysis patients only), Lithuania (2007–2009), Macedonia (2008–2009), Norway (2007–2008), Portugal (2007–2008), Romania (2002–2008), Serbia (2007–2009), Slovakia (2005–2007), Slovenia (2007–2008), Spain (1999–2009), and the United Kingdom (1999–2009). Information on the use of antihypertensive mediation was available only for some of the countries (Belarus, Estonia, Spain, Italy, Lithuania, Norway, Portugal, Serbia, Slovenia, and Slovakia). Within this population, information on the use of antihypertensive medication was available for 94.3% of the patients. To show changes in the prevalence of hypertension in Europe over time, only those countries were included for which data were available from 1999 until 2008, namely Finland, Italy, Spain, and the United Kingdom. Blood pressure reference values in children depend on age, height, and sex and therefore no single cutoff level for hypertension in children and adolescents can be determined. Following the methods published in the NHBPEP Fourth report, we calculated systolic and diastolic blood pressure SDS for each subject, thereby adjusting for age, sex, and height (heights below -3SDS were converted into -3SDS (ref. 16.van Stralen K.J. Jager K.J. Schaefer F. et al.Suggested revision of the NHBPEP blood pressure standardization for growth retarded children.Pediatr Nephrol. 2010; 26: 819-820Crossref PubMed Scopus (7) Google Scholar)). Hypertension was defined as either systolic or diastolic blood pressure ≥95th percentile (SDS≥1.65) for age, height, and sex or when using antihypertensive medication, according to the NHBPEP definitions.17.National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents The fourth report on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents.Pediatrics. 2004; 114: 555-576Crossref PubMed Scopus (5212) Google Scholar Patients were excluded if information on the use of antihypertensive medication was unavailable. Patients with a systolic or diastolic blood pressure ≥95th percentile were considered to have uncontrolled hypertension, irrespective of whether information on antihypertensive medication was present. The SDS for height, weight, and BMI were all calculated using the Centers for Disease Control and Prevention growth charts.18.Kuczmarski R.J. Ogden C.L. Guo S.S. et al.2000 CDC Growth Charts for the United States: methods and development.Vital Health Stat. 2002; 11: 1-190Google Scholar BMI ≥85th percentile for age and sex was defined as overweight, and BMI ≤5th percentile as underweight. To determine the development of hypertensive status in each treatment modality group, we selected only those patients who had a measurement within the first 3 months after initiation of RRT. Furthermore, at least three blood pressure measurements needed to be available in the first 3 years since the initiation of their treatment modality. All patients were required to have at least one measurement within the first 3 months after initiation of that treatment modality. Information was available for 76 HD patients, 183 PD patients, and 66 transplant patients. Renal diseases were grouped by primary renal disease code for pediatric patients, according to the ERA-EDTA Registry coding system19.ERA-EDTA Registry Annual Report 2007 Academic Medical Centre, Department of Medical Informatics. ERA-EDTA Registry: Amsterdam, The Netherlands2009Google Scholar (see Supplementary Appendix S1 online). Observations of one individual over time are not independent but correlated.20.Twisk J.W.R. Applied Longitudinal Data Analysis for Epidemiology: A Practical Guide. Cambridge University Press, Cambridge, UK2003Google Scholar Within the 15 European countries participating in this study, longitudinal data were assembled. To address the fact that a patient might be hypertensive on some measurements but not others, and that not all patients had the same number of measurements, every measurement was divided by the total number of measurements for that patient. For example, if a patient had one hypertensive measurement and one normotensive measurement, he was counted as 1/2 patient in the hypertensive group and 1/2 patient in the normotensive group. To calculate unadjusted and adjusted blood pressure SDS, we performed a linear mixed model analysis. Linear mixed model analysis allows adjustment for the number of measurements taken for every individual patient, and simultaneously for different variables,21.Wist B.T. Welch K.B. Galecki A.T. Linear Mixed Models. Chapman & Hall, CRC, Florida2006Google Scholar using all of the available information. The relationship between hypertension and potential correlating variables was examined and adjustments were made for the following variables: sex, age, primary renal disease, treatment modality at time of blood pressure measurement, and time on RRT. Standardized SDS blood pressure values were recalculated using the distribution of all cases. To calculate the adjusted values for being on antihypertensive medication versus not being on antihypertensive medication, we performed a logistic mixed model analysis, with the same adjustments as prescribed for the linear mixed model analysis. Statistical analyses were performed using the SPSS software version 18.0 (SPSS, Chicago, IL) and SAS 9.2 (SAS Institute, Cary, NC). P values <0.05 were considered statistically significant. The ESPN/ERA-EDTA Registry is funded by the European Society of Pediatric Nephrology (ESPN), the European Renal Association and European Dialysis and Transplant Association (ERA-EDTA), and the NephroQUEST project. The NephroQUEST project has received funding from the European Union in the framework of the Public Health Program (project number 2006114). Furthermore, Amgen has provided an unrestricted educational grant to assist the ESPN in the financial support of the Registry. We thank the patients, their parents, and the staff of all the dialysis and transplant units who have contributed data via their national registries and contact persons. We also thank P Cochat, R Coppo, and D Haffner for being members of the ESPN/ERA-EDTA Registry Committee, D Shitza, R Kramar, R Oberbauer, S Baiko, A Sukalo, K van Hoeck, F Collart, JM des Grottes, R Lombaerts, D Pokrajac, D Roussinov, Z Puretić, D Batinić, K Vondrak, J Heaf, U Toots, P Finne, C Grönhagen-Riska, C Holmberg, C Couchoud, P Niaudet, L le Mignot, E Sahpazova, G Gersdorf, C Scholz, G Ioannidis, G Reusz, S Túri, L Szabó, T Szabó, F Paglialonga, S Picca, E Vidal, A Jankauskiene, S Pavićević, T Leivestad, D Brackman, A Zurowska, I Zagozdzon, C Mota, M Almeida, C Afonso, G Mircescu, L Garneata, E Podgoreanu, M Gafencu, EA Molchanova, NA Tomilina, BT Bikbov, A Peco-Antic, M Kostic, B Spasojevic-Dimitrijeva, D Paripovic, L Podracka, G Kolvek, J Buturovic-Ponikvar, N Battelino, A Alonso Melgar, and the Spanish Pediatric Registry, S Schön, J KG Prütz, A Seeberger, L Backmän, M Herthelius, CE Kuenhi, E Maurer, A Hoitsma, A Hemke, WF Tromp, N Schoenmaker, R Topaloglu, D Ivanov, D Ansell, and C Inward for contributing data to the ESPN/ERA-EDTA Registry. Appendix S1. ERA-EDTA Registry grouped coding system for Primary Renal Diseases. Appendix S2. Systolic blood pressure levels by treatment modality and age groups. Box plots show the median, the 25th and 75th percentile and the 5th and 95th percentile. The red lines indicate the cut-off values of hypertension for boys with a mean age in that particular group with a height at the 25th percentile. Supplementary material is linked to the online version of the paper athttp://www.nature.com/ki
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