Quality of care and monitoring in paediatric end stage renal disease
van Huis, M.
Publication date
2016
Document Version
Final published version
Link to publication
Citation for published version (APA):
van Huis, M. (2016). Quality of care and monitoring in paediatric end stage renal disease.
General rights
It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s)
and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open
content license (like Creative Commons).
Disclaimer/Complaints regulations
If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please
let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material
inaccessible and/or remove it from the website. Please Ask the Library: https://uba.uva.nl/en/contact, or a letter
to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You
will be contacted as soon as possible.
CHAPTER 4
L.C. Dobrowolski*, M. van Huis*, J.H. van der Lee, H. Peters Sengers, M.R. Lilien, K. Cransberg, M.R. Cornelissen,
A.H. Bouts, J.W. de Fijter, S.P. Berger, A.D. van Zuilen, A. Nurmohamed, M.H.G. Betjes, L. Hilbrands, A.J. Hoitsma,
F.J. Bemelman, C.T.P. Krediet and J.W. Groothoff
Nephrology Dialysis Transplantation – accepted for publication April 2016
Epidemiology and management
of hypertension in paediatric and
young adult kidney transplant
recipients in The Netherlands
ABSTRACT
Introduction
Hypertension in kidney transplant recipients (KTRs) is a risk factor for cardiovascular mortality and graft loss. Data on the prevalence of hypertension and uncontrolled hypertension (uHT) in paediatric and young adult KTRs are scarce. Also, it is unknown whether ‘transition’ (the transfer from paediatric to adult care) influences control of hypertension. We assessed the prevalence of hypertension and uHT among Dutch paediatric and young adults KTRs and analysed the effects of transition. Additionally, we made an inventory of variations in treatment policies in Dutch transplant centres.
Methods
Cross-sectional and longitudinal national data from living KTRs ≤30 years (≥1yr post-transplant, eGFR>20ml/min) were extracted from the ‘RICH Q’ database, which comprises information about all Dutch KTRs aged <19yrs, and the Netherlands Organ Transplant Registry database for adult KTRs (≥18-30yrs). We used both upper limit blood pressure (BP) thresholds for treatment according to KDIGO guidelines. uHT was defined as a BP above the threshold. A questionnaire on treatment policies was sent to paediatric and adult nephrologists at 8 Dutch transplant centres.
Results
Hypertension and uHT were more prevalent in young adult KTRs (86.4% and 75.8%) than in paediatric KTRs (62.7% and 38.3%) according to the KDIGO definition. Time after transplantation was comparable between these groups. Longitudinal analysis showed no evidence of effect of transition on systolic BP or prevalence of uHT. Policies vary considerably between and within centres on definition of hypertension, BP measurement and antihypertensive treatment.
Conclusion
Average BP in KTRs increases continuously with age between 6 and 30 years. Young adult KTRs have significantly more uHT than paediatric KTRs according to KDIGO guidelines. Transition does not influence prevalence of uH
4
INTRODUCTION
Hypertension after kidney transplantation increases the risk of cardiovascular disease (CVD) and has disadvantageous effects on allograft function in adults as well as in children [1-6]. Though outcomes such as CVD are not frequently manifested in paediatric patients, the risk for CVD at older age is established early in childhood. Long-term follow-up studies show that CVD accounts for over 40% of premature deaths in patients with paediatric onset of end-stage renal disease [7,8]. Recent data demonstrates that improvement of cardio-protective management, especially antihypertensive treatment, lowers the risk for cardiovascular comorbidity and mortality. Uncontrolled hypertension, defined as persistent blood pressure (BP) measurement above the target value with or without being treated, is an established risk factor contributing to CVD and is therefore regarded as a potential target to ameliorate the prognosis of transplant patients [9,10]. In kidney transplant recipients (KTRs), the reported prevalence of hypertension varies from 59% in children to up to 85% in older adults [1,11-15]. However, these data are derived from large registry databases and mostly based on single BP measurements. To our knowledge, data on prevalence rates of hypertension and uncontrolled hypertension in paediatric KTRs are scarce and those of that for young adult KTRs (aged 18-30 yrs) are hardly available.
The variation in reported prevalence may be caused by a difference in definitions used for hypertension. For adult KTRs, the Kidney Disease Improving Global Outcome (KDIGO) guideline recommends maintaining BP below 130/80mmHg [16]. However, by the WHO guidelines, this level is regarded as the threshold for pre-hypertension and the WHO defines genuine hypertension as BP measurements of 140/90mmHg and above, irrespective of treatment [16-18]. For children, the National High Blood Pressure Education Program (NHBPEP) recommends the p95 upper limit for both systolic and diastolic BP as the threshold to define genuine hypertension and the p90 upper limit for so-called pre-hypertension that does not warrant medical treatment [19]. In contrast, the KDIGO guideline recommends using the p90 upper limit as threshold for medical treatment of high BP in children with renal failure, based on evidence derived from the Effect of Strict BP Control and angiotensin converting enzyme (ACE) Inhibition on the Progression of Chronic Renal Failure in Pediatric Patients (ESCAPE) study [17,20].
Furthermore, the effect of ‘transition’ from paediatric to adult care around the age of 18 years is believed to be associated with a reduced adherence to medication regimens. Transition might therefore lead to a reduction in the control of hypertension [21-25]. To what extent transition affects the prevalence of uncontrolled hypertension in young KTRs is unknown. Earlier studies showed that different management policies among centres and countries affect outcome in children with chronic kidney disease [26-28]. Policy variation in the post-transplant antihypertensive care has not been studied.
In this study we aimed to assess the prevalence and differences in prevalence of hypertension and uncontrolled hypertension (uHT) between paediatric and young adult KTRs using
different BP thresholds for defining hypertension. Furthermore, we aimed to assess the effect of transition on BP and treatment of hypertension. Finally, we made an inventory differences in antihypertensive treatment policies among adult and paediatric nephrologists.
METHODS
For performing cross-sectional and longitudinal analyses, we extracted data from the ‘Renal Insufficiency Therapy in CHildren – Quality assessment and improvement project’ (RICH-Q) for the paediatric patients and data from the Netherlands Organ Transplant Registry (NOTR) for adult patients. Patients were stratified by age in 5 groups: children aged 4-6 years, 7-12 years, 13-17 years, and young adults aged 18-24 years and 25-30 years. The RICH-Q project is a multicentre registry including all patients with ESRD aged <19 years. Data have been prospectively collected from October 2007 onwards in all Dutch, Belgian and 3 German paediatric nephrology centres. For this study only Dutch data were used. The NOTR database is a nationwide registry containing anonymised data since 1968 of all patients who underwent organ transplantation. Both registries comprise longitudinal information on demographics, transplantation details, recipient and donor characteristics, body composition, BP and rejection episodes and medication.
For cross-sectional and longitudinal analyses, we included KTRs with eGFR ≥20ml/min and with a transplant vintage of ≥1yr, since stable BP control is often not achieved within the first year post-transplant. Data were retrieved on May 28th 2014, using the latest available visit
registration of patients who were at the retrieval date. Since the NOTR database records plasma creatinine and not eGFR, we calculated eGFR using the Modification of Diet in Renal Disease (MDRD) equation as well as the Schwarz formula for adults to compare kidney function in children and adults [29,30]. Missing values for heights in adults were imputed with the mean for >18 year-old males (mean 175.2 cm) and females (mean 162.0 cm) to calculate eGFR using the Schwartz formula. Children with missing height values were excluded. Reference values of healthy age-matched children were used to define BP targets. BP for paediatric KTRs are expressed in percentiles based on general population values for age, sex and height [19,32].
For the effect of transition on BP and uHT, we acquired longitudinal data of individual KTRs with a transplant ≥1yr, eGFR ≥20ml/min, and aged ≤30yrs on May 28th 2014. All their
available records were included. Data from both databases were merged using transplant identification numbers. From these records, we selected a cohort of patients who had a minimum of two BP recordings both before and after the transition moment, defined as the date on which the treating paediatric nephrologist had ended the registration in the RICH-Q registry.
Hypertension definitions
Table 1 provides an overview of the 2 different thresholds for ‘hypertension’. 1. A BP above the defined threshold at which anti-hypertensive treatment is recommended, used in KTRs
4
for both children and adults, i.e. the KDIGO guideline for BP management in patients with chronic renal disease and renal transplant recipients, version 2012. 2. The WHO (adult guidelines) and 4th Pediatric Task Force NHBPEP 2004 guideline on hypertension in the
general population. The threshold according to the KDIGO guidelines is consistent with p90 values according to WHO/Task force. [16-18,31-35]. Firstly, we defined hypertension as BP above the recommended threshold and normal BP with anti-hypertensive treatment. This includes all patients except for normotensive patients without antihypertensive treatment. Also, we use the terms ‘controlled hypertension’ and ‘uncontrolled hypertension’. Systolic BP (SBP) and/or diastolic BP (DBP) persistently measured below target values while treated with one or more antihypertensive agents is defined as controlled hypertension.
Uncontrolled hypertension (uHT) is a BP above the recommended threshold with or without therapy (uHT treated vs. uHT untreated). Normotension is defined as a BP below
target values without treatment.
We inventoried treatment policies among 8 adult and 4 paediatric nephrology centres using an online questionnaire, which was developed in collaboration with paediatric and adult nephrologists to ensure content validity. The questionnaire included questions on local official (written) protocols for post-transplant hypertension treatment, on methods of BP measurement, frequency of screening for hypertension, BP registration, and definitions of hypertension, estimated prevalence rates and on preferences in antihypertensive drugs (Appendix). The physician in charge of every academic adult and paediatric kidney transplant centre received the request to distribute the questionnaire among their transplant nephrologists.
Statistical analysis
Statistical analyses were performed using IBM SPSS Statistics 21.0 (IBM Corp, USA). Non-normally distributed data are presented as medians with interquartile ranges (IQR). P-values below 0.05 are considered statistically significant. Growth models were performed using Mplus 7.0 (Muthén&Muthén, USA) [36], to examine individual development over time. Two ‘piecewise growth models’ were used: 1. Individuals’ development of systolic BP (continuous variable), and 2. Individuals’ development of hypertension over time (dichotomous variable). We used the moment of transition as initial status or ´intercept´. Two piecewise random slopes were calculated and compared: the first random slope represents the average ‘growth’ rate (i.e. increase in mmHg or uHT risk) per year until the moment of transition; and the second slope represents the average ‘growth’ rate per year from transition onwards.
RESULTS
Data from 640 paediatric and adult patients aged ≤30yr with a functioning graft were available on May 28th, 2014. 174 subjects were excluded for meeting the exclusion criteria:
missing heights for children (n=4); missing creatinine data (n=3); eGFR ≤20 ml/min (n=55); leaving 466 patients for analysis. Patient characteristics are given in Table 2.
Prevalence of hypertension and uncontrolled hypertension
Figures 1 and 2 show the prevalence of hypertension and uHT. In Figure 2 the classification is divided into normotension (BP under target without treatment), hypertension with treatment (BP under target level with treatment) and treated and untreated uHT. Hypertension according to KDIGO was significantly more prevalent in young adult patients than in paediatric KTRs (86%, 95% CI 82-90% vs. 76%, 95% CI 67-82%; p=0.007). When the WHO/Task Force thresholds were used, the difference in hypertension between adult (72.0%, 95% CI 67-76%) and paediatric (70.0%, 95% CI 61-77%) KTRs was smaller and not significant, p=0.681.
UHT, according to KDIGO, was also more prevalent in young adult patients (63.0%, 95% CI 58-68%) as compared to paediatric KTRs (38.3%, 95% CI 30-47%, p<0.0001). The prevalence of uHT according to WHO/NHBPEP was also statistically different between children (7.5%, 95% CI 4-14%) and adults (24.0%, 95% CI 20-29%, p<0.001), but showed a U-shape curve when all age groups were compared, with the highest percentages in patients of 4-6 yrs (25.0%, 95%CI 10-50%) and 25-30 yrs (30.4%, 95%CI 24-38%) and the lowest in patients 13-17 yrs (1.6%, 95% CI 0-9%) (p<0.001 between groups).
In 11 (23%) paediatric patients with uHT (n=7, aged 7-12yrs, n=4, 12-17yrs) no antihypertensive agents were prescribed. In 87 (42%) adult patients (n=38, 22% aged 18-24yrs, n=49, 20% aged 25-30 yrs) no antihypertensive drug was registered while having uHT. Table 3 demonstrates the BP and its regulation.
Figure 3 presents the mean systolic BP with 95% CI in the cross-sectional analysis, showing a higher BP in older patients.
Transition
Criteria for inclusion in the longitudinal analysis were met in 105 patients. Figure 4 presents the development of the average SBP in the 5 years before and 5 years after transition. The mean intercept at transition (t=0) was 124.5 mmHg (95% CI 122.4-126.6) for systolic BP. Before transition, the average change in systolic BP per year was not significantly different from zero with 0.11 mmHg (95% CI -0.50 - 0.72). After transition, SBP significantly decreased by 0.80 mmHg (95% CI -1.58 - 0.02) per year. There was no statistically significant effect of transition on the risk of uHT 5 years before and 5 years after transition. Before transition, the slope over the 5 year period, indicating the risk change was -0.1% (95% CI -7.9% - 7.7%) whereas in the 5 year period after transition, the risk of uHT increased but not significantly (2.6%, 95% CI -6.2% - 11.2%).
Policies
All 4 paediatric and 7 out of 8 adult centres and their member nephrologists responded to the questionnaire. Response rates were not assessed since the number of physicians receiving
4
the questionnaire per centre was not known. Results are described in Table 4. Written official policies on antihypertensive treatment were available in 2/4 paediatric and in 6/7 adult centres. BP measurements are performed at every visit in all centres. In paediatric departments, a nurse performs all BP measurements. While in the adult centres, BP is measured by the physician in 4/7, and by a nurse in 3/7. Adult patients also measure themselves at 2 of the 7 centres. In all paediatric centres and according to 16 adult nephrologists, BP is measured in sitting position. Three adult nephrologists measure BP in supine position. The number and duration of BP measurements varies from one single measurement to 15min continuous measurements. The BP registered in the medical chart varies between listing ‘each individual measurement’ (7 adult, 2 paediatric nephrologist), the lower of 2 measurements (7 adult, 1 paediatric) or the mean of 2 or 3 measurements (3 adult, 1 paediatric nephrologist). Two adult nephrologists reported not to know which BP is registered. Hypertension is defined by 11 adult nephrologists as BP >130/80mmHg, by 4 as >130/90mmHg, by 1 as >135/85mmHg and by 3 as >140/90mmHg. The BP threshold of p90 is used by 2 paediatric nephrologists, 2 use p95 as threshold. First choice antihypertensive agents by both adult and paediatric nephrologists were calcium antagonists and ACE-inhibitors. Although beta-blockers were not included in top three choices of antihypertensive agents in children, according to the registry in 26% of the KTRs aged 13-17 years beta-blockade was prescribed. Paediatric nephrologists estimated the prevalence of hypertension to be 40% [IQR 23-50%], adult nephrologists 70% [IQR 50-75%].
DISCUSSION
This is the first study that addresses prevalence rates of hypertension and uHT in paediatric as well as young adult KTRs and assesses the effect of transition. We show that the prevalence of hypertension and uHT in children and young adult KTRs in the age range of 4 to 30 years tends to be higher in the relatively older subjects, which is comparable with other literature [37,38]. Uncontrolled HT, meaning untreated or undertreated hypertension, shows a high prevalence, especially among young adult KTRs. We also demonstrate the difference in hypertension prevalence using KDIGO and WHO/Task Force definitions. Transition from paediatric to adult nephrology care did not show any influence on BP. We also demonstrate a wide variation in frequency and methods of BP measurements and official policies on antihypertensive treatment within and between centres and between paediatric and adult nephrologists.
In the general population, BP as well as the prevalence of hypertension increases with age [39]. However, between 15 and 40 years, systolic BP remains stable in healthy subjects [40-43]. In contrast to this, we found an increasing systolic BP in KTRs at a younger age (25-30 years). This suggests that apart from the physiological increase in systolic BP over time, an additional mechanism causes a BP increment in KTRs. This is probably due to hypertension-inducing factors such as arterial stiffness and immunosuppressive use, related to transplant and chronic kidney disease (CKD).
The difference in prevalence of hypertension among the age groups might be due to a difference in primary renal disease or the cumulative duration of renal replacement therapy rather than the differences in management policies. However, although these factors were not included in the analysis, the time after transplantation has been comparable and the linear association between age and increase of systolic BP suggests that the susceptibility to vascular stiffening in CKD patients increases with age.
In particular, the young adult KTRs were often undertreated according to both the KDIGO guidelines and, to a far lesser extent, the WHO guidelines. This under-treatment can partly be explained by the inconsistency in the official recommendations, which is also reflected in the variety in management policies that we found among physicians. Explicitly, KDIGO 2009 guidelines recommend thresholds for the treatment of high BPs at levels equal to so-called pre-hypertension in non-renal patients for adults as well as for children [17]. The evidence for the downward adjustment to the p90 and 130/80 thresholds is based on observational studies and evidence from CKD non-dialysis (ND) dependent patients. As is stated in KDIGO 2009 ‘In KTRs, there is little reason to believe that the prevention and treatment of hypertension would not also prevent CVD and kidney allograft injury’. In the 2012 revision of KDIGO, however, the recommendation for CKD transplant children had disappeared, but the overall recommendation for BP management in CKD ND children - the same p90 recommendation - had been upgraded to level 1c, based on the ESCAPE studies [16]. The confusion derives from the paucity of evidence on the beneficial effects of anti-hypertensive treatment on CVD and graft outcome. This applies to adults as well as children. As the majority of transplanted patients have a degree of CKD, there is a motive to apply non-dialysis dependent CKD guidelines for hypertension management to this group of patients. It emphasizes the need for long-term studies in paediatric and young adult KTRs to estimate the effect of BP on cardiovascular outcome.
We could not find a negative effect of transition from paediatric to adult care on the prevalence of uncontrolled hypertension. Transition is a concern since it may lead to a presumed reduced adherence to the prescribed therapy as a result of a different, on average less directive, patient approach from adult nephrologists compared to paediatric nephrologists. Less therapy adherence might induce a higher prevalence of hypertension and periods of rejection [44]. Samuel et al. found an adjusted hazard ratio for graft loss within the adaptation period after transition compared with the period before transition of 2.24 (95%CI 1.19-4.20) [45].) However, the crude failure rate of 6.6 per 100 person-years of losing the graft within the adaptation period of 2.5 years after transition was only slightly higher than after the adaptation period (i.e. for young adults), in which the crude failure rate was 5.1 per 100 person-years. Watson et al. reported that 40% of young adults (age range 15.7 – 20.9 years) lost their renal graft within 36 months of transition [24]. However, this retrospective study included only 20 patients of which the majority (5/7) of patients with a rejection had psychosocial difficulties identified prior to transplantation. Moreover, in 4/7 patients low immunosuppressive levels were found, which may be due to non-adherence, but may also be caused by insufficient dosages. Not all studies support these effects of transition: Van den Heuvel et al. showed no increased risk of rejection or graft failure after transition
4
[46]. Although we do not have data on therapy adherence, our data imply that there is no adverse effect from transition on BP control and therefore there is most likely no adverse effect on adherence to anti-hypertensive medication either.
Policies
In this study we also found differences in policies, definitions and management of hypertension after renal transplantation. Previous studies have also shown a considerable variation in management policies among centres for paediatric dialysis and transplantation [26-28,47]. As shown in this study, paediatric and adult nephrologists have different management policies for post-transplant hypertension. We believe that this inconsistency in management of hypertension in the clinical practice is rooted in the absence of prospective studies from which clear guidelines can be formed for this specific patient group. It is likely that the policy variation contributed to the differences in prevalence of (uncontrolled) hypertension but we could not study this since both registries contain anonymised data and therefore we were unable to trace which patient is treated by which centre or physician. Adult nephrologists gave a better estimation of the ‘true’ prevalence than paediatric nephrologists. This may be due to a higher awareness and prevalence of vascular disease and hence of hypertension among adult KTRs. The exact indication for a prescribed drug was not registered. We were aware of the potential overestimation of antihypertensive agents since e.g. ACE inhibitors are more likely to be prescribed for other indications (e.g. proteinuria reduction) than for hypertension. Calcium antagonists and ACE-inhibitors were preferred for primary treatment, but there was considerable heterogeneity. These variations in preferred antihypertensive treatment are a consequence of the absence of recommendations for pharmacological treatment in present guidelines
LIMITATIONS
This study has several limitations. Firstly, there were small numbers of patients available, especially in the youngest groups of 4-6 yrs and 7-13 yrs. However, this is currently the largest Dutch cohort available. The level of treatment success could not be assessed, since we were not informed about medication dosage or medication adherence. Due to the relatively small number of patients in the longitudinal analysis, the distribution of the average SBP in the 5 years before and 5 years after is large. Moreover, we considered those patients receiving treatment with antihypertensive agents as having hypertension. We were aware that some antihypertensive drugs are prescribed for other medical symptoms or conditions than hypertension, such as ACEi for proteinuria. Moreover, we noticed that 24-hour blood pressure measurements would give better indications of true blood pressure courses. However very few of these records are available in the registry since they are not routinely performed in children nor in young adult KTRs.
Although we used all available follow-up data, we cannot rule out the possibility that a proportion of less adherent patients is not included in the analysis. However, we know that
is up to 95%. We could not assess response rates on the questionnaire since the head of each department distributed the questionnaires among the transplant nephrologists and the number of informed physicians remains unknown. Moreover, we used data in which we could not verify the accuracy and differences in methods and in registration accuracy between physicians and between centres. Finally, in the questionnaire we did not discriminate between differing times after transplantation (we included patients from one year after transplant and beyond). This may influence results, as patients with hypertension shortly after transition, are treated different compared to those with a longer follow up after transplantation.
CONCLUSION
Hypertension and uHT after kidney transplantation is more common in subjects between 25 and 30 years than in younger subjects. The transfer from paediatric to adult care does not influence BP or hypertension prevalence. Policies regarding BP targets and methods of BP measurements vary among the treating physicians, both within and between groups of adult and paediatric nephrologists. Close attention to BP regulation is needed, especially in young adult KTRs.
Acknowledgements
We gratefully thank M. Leegte and C. Konijn for their support in the data collection from the registry databases, especially M. Leegte for the technical support. We thank A.H.M. Bouts, M. R. Lilien, L. Koster and K. Cransberg for assisting in the development of the questionnaire. We highly appreciate the contribution of all nephrologists who completed the questionnaire.
CTPK is supported by grants IP-11.40 and KJPB12.29 from the Dutch Kidney Foundation and ZonMW Clinical Fellowship (40007039712461), which are gratefully acknowledged.
Conflict of interest statement
All authors declare that the results presented in this paper have not been published previously in whole or part.
4
TABLES
Table 1 Blood pressure thresholds to define hypertension
Patients Hypertension definition: BP target Guideline I Pediatric KTRs ≤18yr office-based SBP or
DBP >p90 (or +2SD)* KDIGO 2009
I Adult KTRs >18yr office-based SBP >130 and/or DBP >80 mmHg
KDIGO 2009+2012 UK RA 2010 KHA-CARI 2011 KDOQI 2010
II Children ≤18yr** ≥p95 (or +2.5 SD)* 4th Pediatric Task Force NHBPEP 2004
II Adults > 18yr** > 140/90 mmHg‡ WHO ESH 2013 JNC8
The ERBP, ESPN nor KDIGO 2012 have guidelines for BP control in pediatric KTRs. * for age, sex and height (using the 50th percentile)
** not transplant specific
‡ no specific advices for KTRs, for CKD stages 3 and higher BP < 140/90mmHg
SBP systolic BP, DBP diastolic BP, KHA-CARI: Kidney Health Australia Caring or Australasians with Renal Impairment, ERBP: European Renal Best Practice position statement guideline 2009; KDIGO Kidney Disease: Improving Global Outcomes (from: Clinical Practice Guideline for the Management of Blood Pressure in Chronic Kidney Disease 2012); NHBPEP National High Blood Pressure Educa-tion Program; UK RA :United Kingdom Renal AssociaEduca-tion; WHO World Health OrganisaEduca-tion ESH European Society of Hypertension and European Society of Cardiology
T able 2. P atient c har acteristics 4-6 y ears n=16 7-12 y ears n=43 13-17 y ears n=61 18-24 y ears n=175 25-30 y ears n=171 Demogr aphics Gender (male) n, (%) 14 (88) 24 (56) 34 (56) 103 (59) 100 (59) Age (yrs) 5.5 ± 0.8 10.3 ± 1.8 16.3 ± 1.4 21.8 ± 22.1 27.6 ± 1.3 Ethnicity Caucasian 12 (75) 31 (72) 24 (65) No data No data W eight SDS -0.3 [-1.0-0.8] -0.1 [-0.9- 0.8] -0.8 [-1.2-0.4] -0.3 [-1.0.-1.4] 0.6 [-0.4-1.3] Height SDS -0.9 [-1.6 - -0.2] -1.1 [-1.8- -0.7] -1.3 [-1.9- -0.6] -1.4 [-2.4- -0.4] -0.9 [-1.7- -0.1]
Body Mass index SDS
0.6 [0.1-1.1] 0.5 [-0.1-1.5] 0.4 [-0.2-1.2] 1.0 [-0.2-2.0] 1.1 [0.2-1.9] Age at Tx (yrs) 3.0 [2.0-3.8] 7.0 [5.0-8.0] 12.0 [9.5-14.0] 17.0 [13.0-19.0] 23.0 [19.0-25.0] T ime after Tx (yrs) 2.5 [2.0-3.0] 4.0 [3.0-5.0] 5.0 [3.0-10.0] 5.0 [3.0-11.0] 4.0 [2.0-9.0]
Donor type (living)
n, (%) 11 (69) 21 (49) 31 (51) 113 (65) 112 (66)
Donor age (yrs)
40 [33-44] 43.0 [36-54] 43 [31-51] 47 [40-52] 48 [42-54] Gr aft function
Plasma creatinine (µmol/L)
64 [46-80]
87 [66-112]
113 [92-137]
129.0 [103-174]
132 [117-158]
eGFR Schwartz (ml/min) †
63 [50-81] 61 [43-74] 53 [45-65] 49 [36-58] 47 [39-54] eGFR MDRD (ml/min) 54 [39-65] 49 [40-61] Proteinuria (g/L) 0.10 [0.06-0.31] 0.10 [0.07-0.15] 0.12 [0.09-0.22] 0.15 [0.06-0.32] 0.2 [0.09-0.50] Immunosuppression Mycophenolate ** 12 (75) 21 (49) 36 (59) 104 (62)* 97 (59)* Prednisolone (%) 7 (44) 31 (72) 40 (66) 134 (80)* 146 (79)* T acrolimus (%) 15 (94) 38 (88) 44 (72) 103 (62)* 94 (55) Azathioprine (%) 1 (6) 1 (2) 4 (7) 25 (15) 27 (17)* Cyclosporine (%) 1 (6) 1 (2) 10 (16) 22 (13)* 12 (7)* mT OR (sirolimus/everolimus) (%) 0 5 (12) 4 (7) 8 (5)* 13 (8)* Tx=tr
ansplantation SDS= Standard Deviation Score
†Sc
hw
artz formula: when height w
as missing in adults KTRs,
the mean height of 18 y
ear old KTRs w as used. **Mycophenolate is either m ycophenolate acid or m ycophenolatemofetil. * v
alid percent: for 18-24yr
s 8 missings,
for 25-30yr
s 9 missing v
alues.
The percentage of the group of whic
h the data w
as known is presented.
unknown v
alues: n=16,
n=73 n=170 for age groups 13-17yr
s, 18-24r s and 25-30yr s respecti vel y.
4
T
able 3.
Blood pressure and blood pressure regulation
Blood pressure 4-6 y ears n=16 7-12 y ears n=43 13-17 y ears n=61 18-24 y ears n=175 25-30 y ears n=171 Systolic BP in percentiles 76 [39-94] 81 [54-94] 83 [62-96] 81 [55-96] 84 [93-98] Diastolic BP in percentiles 81 [61-99] 73 [49-90] 68 [45-80] 64 [39-87] 77 [57 -94] Z score systolic BP 0.7 [-0.3-1.6] 0.9 [0.1-1.6] 1.0 [0.3-1.8] 0.9 [0.1-1.8] 1.0 [0.3-2.] Z score diastolic BP 0.8 [-0.1-1.89] 0.6 [-0.03-1.3] 0.5 [-0.1-0.8] 0.4 [-0.3-1.1] 0.7 [0.2-1.6] Systolic of fice BP (mmHg) 102 [93-109] 110 [104-116] 122 [116-131] 125 [117-130] 130 [120-138] Diastolic of fice BP (mmHg) 63 [53-77] 66 [60-74] 70 [65-75] 76 [70-82] 80 [74-86] Pulse pressure (mmHg) 36 ± 7 43 ±8 53 ± 10 48 ± 12 48 ± 46 SBP above target I* n, (%) 5 (31) 14 (33) 39 (64) 66 (38) 85 (50)
DBP above target II*
n, (%) 5 (31) 8 (19) 3 (5) 74 (42) 105 (61) SBP above target I ** n, (%) 4 (25) 7 (16) 17 (28) 23 (13) 39 (23)
DBP above target II** n,
(%) 4 (25) 4 (9) 1 (2) 17 (10) 32 (19) Antih ypertensi ve treatment
Antihypertensive drug use
n, (%) 9 (56) 26 (61) 44 (72) 104 (60) 122 (71) zero antihypertensives n, (%) 7 (44) 17 (40) 17 (28) 70 (40) 49 (29) 1-3 antihypertensives, n, (%) 9 (56) 26 (61) 44 (72) 103 (59) 119 (69) >4 antihypertensive, n, (%) 0 0 0 1 (1) 3 (2) A T II blocker or A CEi, n, (%) 4 (25) 12 (26) 23 (38) 50 (29) 47 (28) Betablocking agent n, (%) 1 (5) 5 (12) 16 (26) 38 (22) 71 (42) Calum-antagonist n, (%) 6 (38) 17 (40) 30 (49) 55 (31) 60 (35) Diuretic n, (%) 0 2 (5) 6 (10) 17 (10) 26 (14)
Other antihypertensive drug
n, (%) 0 0 0 1 (1) 7 (4)
BP= blood pressure * BP threshold KDIGO guideline: p90 for height,
sex and age for c
hildren and BP threshold 130/80mmHg for adults
≥
18yr
s
** BP threshold
WHO/T
ask Force: p95 for height,
sex and age for c
hildren and BP threshold 140/90mmHg for adults
≥
18yr
Table 4 Results of the questionnaire on post-transplant antihypertensive policies.
Pediatric centers 1 2 3 4
Respondents 1 1 1 1
Official policy Yes No Yes No
Written Policy yes unknown yes unknown
Policy base‡ D CD B B
Screening frequency every visit every visit every visit every visit
Position sitting sitting sitting sitting
Method BP automatic automatic automatic manual
1st choice CA unknown ACEi CA
2nd choice Diuretic unknown ATII block Diuretic
3rd choice Alpha block unknown Alpha block ACEi
Adult centers 1 2 3 4 5 6 7
Respondents 5 2 5 3 1 2 1
Official Policy Yes 5 0 2 3 0 1 1
No 0 2 3 0 1 1 0
Written Policy Yes 5 0 2 3 0 0 1
No 0 0 3 0 0 2 0 Policy base‡ 1xA, 1xBCE, 2xBD, 1xBE 1xBCD, 1xCD 1xBCE, 1xBED, 1xC, 1xD, 1xDE 1xB, 1xABCD, 1xD 1xCD 1xCD, 1xCDE 1xBDE Screening
frequency Every visit 3 2 3 3 1 1 1
1 per 3
mnth 2 0 0 0 0 0 0
Home BP 0 0 2 0 0 0 0
Patients position Sitting 5 2 5 1 1 2 0
Supine 0 0 0 2 0 0 1 Method BP measurement Automatic 4 2 2 0 0 2 0 Manual 0 0 1 3 1 0 1 Dynamap 1 0 0 0 0 0 0 Home BP 0 0 2 0 0 0 0 1st choice antihypertensive CA 5 2 3 2 0 1 1 Beta block 0 0 1 1 1 0 0 ACEi 0 0 1 0 0 1 0 2nd choice CA 0 0 2 1 1 0 0
4
Beta block 1 0 0 2 0 0 1 ACEi 0 2 2 0 0 1 0 Diuretic 4 0 0 0 0 0 0 AT II block 0 0 1 0 0 0 0 3rd choice ACEi 3 0 1 2 1 0 1 Diuretic 0 1 4 1 0 0 0 AT II block 1 1 0 0 0 1 0 Alpha block 1 0 0 0 0 0 0*Only 4 transplant centers have pediatric kidney transplant departments. ‡ A=unknown, B=Interna-tional guidelines, C=Literature, D=Expert opinion, E=NaB=Interna-tional guidelines CA=calcium antagonist, ACEi=angiotensin converting enzyme inhibitor, Beta Bl.=beta blocker, ATII= angiotensin II receptor blocker.
FIGURES
Figure 1.
Hypertension I KDIGO= BP > p90 for children or >130/80mmHg for adults >18yrs and/or treat-ment with antihypertensive agent(s). Hypertension II WHO/Task Force= BP >p95 for children or >140/90mmHg for adults >18yrs and/or treatment with antihypertensive agent(s). Uncontrolled HT I= BP above KDIGO targets, irrespective of treatment with antihypertensive agent(s). Uncontrolled HT II= BP above WHO/Task Force target irrespective of treatment with antihypertensive agent(s)
Figure 2.
Blood pressure regulation Classification of blood pressure above targets. I= KDIGO=BP > p90 for children or >130/80mmHg for adults >18yrs and/or treatment with antihypertensive agent(s). II= WHO/Task Force=BP >p95 for children or >140/90mmHg for adults >18yrs and/or treatment with antihypertensive agent(s). Uncontrolled HT I= BP above KDIGO targets, irrespective of treatment with antihypertensive agent(s). Uncontrolled HT II= BP above WHO/Task Force target irrespective of treatment with antihypertensive agent(s).
4
Figure 3.
Mean systolic BP + 95%CI for kidney transplant recipients (cross sectional)
Figure 4.
REFERENCES
1. Baluarte HJ, Gruskin AB, Ingelfinger JR, Stablein D, Tejani A. Analysis of hypertension in children post renal transplantation--a report of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS). Pediatr Nephrol 1994; 8: 570-573.
2. Kasiske BL, Anjum S, Shah R, et al. Hypertension after kidney transplantation. Am J Kidney Dis 2004; 43: 1071-1081.
3. Mitsnefes MM, Khoury PR, McEnery PT. Early posttransplantation hypertension and poor long-term renal allograft survival in paediatric patients. J Pediatr 2003; 143: 98-103.
4. Ojo AO, Hanson JA, Wolfe RA, Leichtman AB, Agodoa LY, Port FK. Long-term survival in renal transplant recipients with graft function. Kidney Int 2000; 57: 307-313.
5. Opelz G, Wujciak T, Ritz E. Association of chronic kidney graft failure with recipient blood pressure. Collaborative Transplant Study. Kidney Int 1998; 53: 217-222. 6. Seeman T, Simkova E, Kreisinger J, et al. Control of hypertension in children after
renal transplantation. Pediatr Transplant 2006; 10: 316-322.
7. Koshy SM, Guttmann A, Hebert D, Parkes RK, Logan AG. Incidence and risk factors for cardiovascular events and death in paediatric renal transplant patients: a single centre long-term outcome study. Pediatr Transplant 2009; 13: 1027-1033.
8. McDonald SP, Craig JC. Long-term survival of children with end-stage renal disease. N Engl J Med 2004; 350: 2654-2662.
9. Opelz G, Dohler B. Improved long-term outcomes after renal transplantation associated with blood pressure control. Am J Transplant 2005; 5: 2725-2731. 10. Vogelzang JL, van Stralen KJ, Jager KJ, Groothoff JW. Trend from cardiovascular to
non-cardiovascular late mortality in patients with renal replacement therapy since childhood. Nephrol Dial Transplant 2013; 28: 2082-2089.
11. Cameron C, Vavilis G, Kowalski J, Tyden G, Berg UB, Krmar RT. An observational cohort study of the effect of hypertension on the loss of renal function in paediatric kidney recipients. Am J Hypertens 2014; 27: 579-585.
12. Carpenter MA, Weir MR, Adey DB, House AA, Bostom AG, Kusek JW. Inadequacy of cardiovascular risk factor management in chronic kidney transplantation - evidence from the FAVORIT study. Clin Transplant 2012; 26: E438-446.
13. Dobrowolski LC, Bemelman FJ, van Donselaar-van der Pant KA, Hoitsma AJ, ten Berge IJ, Krediet CT. Treatment efficacy of hypertension in kidney transplant recipients in the Netherlands. Neth J Med 2014; 72: 258-263.
14. Kramer AM, van Stralen KJ, Jager KJ, et al. Demographics of blood pressure and hypertension in children on renal replacement therapy in Europe. Kidney Int. 2011;80(10):1092-1098.
4
15. Seeman T. Ambulatory blood pressure monitoring in paediatric renal transplantation. Curr Hypertens Rep 2012; 14: 608-618.
16. Kidney Disease: Improving Global Outcomes (KDIGO) Blood Pressure Work Group KDIGO Clinical Practice Guideline for the Management of Blood Pressure in Chronic Kidney Disease. Chapter 5. Blood pressure management in kidney transplant recipients (CKD T). Kidney Int Suppl 2012; 2: 370-371.
17. Kidney Disease: Improving Global Outcomes (KDIGO) KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant 2009; 9 Suppl 3: S1-155.
18. Whitworth JA. 2003 World Health Organization (WHO)/International Society of Hypertension (ISH) statement on management of hypertension. J Hypertens 2003;21(11):1983-1992.
19. National High Blood Pressure Education Program (NHBPEP)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(2 Suppl 4th Report): 555-576.
20. Wuhl E, Trivelli A, Picca S, et al. Strict blood-pressure control and progression of renal failure in children. N Engl J Med 2009;361(17):1639-1650.
21. Harden PN, Walsh G, Bandler N, et al. Bridging the gap: an integrated paediatric to adult clinical service for young adults with kidney failure. BMJ 2012; 344: e3718. 22. Keith DS, Cantarovich M, Paraskevas S, Tchervenkov J. Recipient age and risk of
chronic allograft nephropathy in primary deceased donor kidney transplant. Transpl Int 2006; 19: 649-656.
23. Kohok DD, Shah S, Kumar R, Venuto L, Gudleski G, Venuto R. Interventions to reduce clinical inertia in cardiac risk factor management in renal transplant recipients. J Clin Hypertens (Greenwich) 2014; 16: 127-132.
24. Watson AR. Non-compliance and transfer from paediatric to adult transplant unit. Pediatr Nephrol 2000; 14: 469-472.
25. Wolff G, Strecker K, Vester U, Latta K, Ehrich JH. Non-compliance following renal transplantation in children and adolescents. Pediatr Nephrol 1998; 12: 703-708. 26. Tromp WF, Schoenmaker NJ, van der Lee JH, et al. Important differences in
management policies for children with end-stage renal disease in the Netherlands and Belgium- report from the RICH-Q study. Nephrol Dial Transplant 2012; 27: 1984-1992.
27. van Huis M, Bonthuis M, Sahpazova E, et al. Considerable variations in growth hormone policy and prescription in paediatric end-stage renal disease across European countries-a report from the ESPN/ERA-EDTA registry. Nephrol Dial Transplant 2015; pii: gfv105. epub ahead of print.
28. van Huis M, Schoenmaker NJ, Groothoff JW, et al. Policy variation in donor and recipient status in 11 paediatric renal transplantation centres. Pediatr Nephrol 2013; 28: 951-957.
29. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med 1999; 130: 461-470.
30. Schwartz GJ, Munoz A, Schneider MF, et al. New equations to estimate GFR in children with CKD. J Am Soc Nephrol 2009; 20: 629-637.
31. Mancia G, Fagard R, Narkiewicz K, et al. 2013 ESH/ESC Guidelines for the management of arterial hypertension: the Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens 2013; 31: 1281-1357.
32. Baker R, Jardine A, Andrews P. Renal Association Clinical Practice Guideline on post-operative care of the kidney transplant recipient. Nephron Clin Pract 2011;118 Suppl 1: c311-347.
33. Bia M, Adey DB, Bloom RD, Chan L, Kulkarni S, Tomlanovich S. KDOQI US commentary on the 2009 KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Kidney Dis 2010; 56: 189-218.
34. Chadban SJ, Barraclough KA, Campbell SB, et al. CARI guideline: KHA-CARI adaptation of the KDIGO Clinical Practice Guideline for the Care of Kidney Transplant Recipients. Nephrology. 2012; 17: 204-214.
35. James PA, Oparil S, Carter BL, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). J Am Medical Assoc 2014; 311: 507-520. 36. Muthén LKaM, B.O. Mplus User’s Guide. Seventh Edition ed. Los Angeles: Muthén
& Muthén; 1998-2012.
37. Gulhan B, Topaloglu R, Karabulut E, et al. Post-transplant hypertension in paediatric kidney transplant recipients. Pediatr Nephrol 2014; 29: 1075-1080.
38. Weir MR, Burgess ED, Cooper JE, et al. Assessment and management of hypertension in transplant patients. J Am Soc Nephrol 2015; 26: 1248-1260.
39. Kotchen JM, McKean HE, Kotchen TA. Blood pressure trends with aging. Hypertension. 1982; 4: Iii128-134.
40. Cheng S, Xanthakis V, Sullivan LM, Vasan RS. Blood pressure tracking over the adult life course: patterns and correlates in the Framingham heart study. Hypertension 2012; 60: 1393-1399.
41. Friedman GD, Cutter GR, Donahue RP, et al. CARDIA: study design, recruitment, and some characteristics of the examined subjects. J Clin Epidemiol 1988; 41: 1105-1116.
42. Kishi S, Teixido-Tura G, Ning H, et al. Cumulative Blood Pressure in Early Adulthood and Cardiac Dysfunction in Middle Age: The CARDIA Study. J Am Coll Cardiol 2015; 65: 2679-2687.
43. Rosen DS, Blum RW, Britto M, Sawyer SM, Siegel DM. Transition to adult health care for adolescents and young adults with chronic conditions: position paper of the Society for Adolescent Medicine. J Adolesc Health 2003; 33: 309-311.
4
44. Forbes TA, Watson AR, Zurowska A, et al. Adherence to transition guidelines in European paediatric nephrology units. Pediatr Nephrol 2014; 29: 1617-1624. 45. Samuel SM, Nettel-Aguirre A, Hemmelgarn BR, et al. Graft failure and adaptation
period to adult healthcare centres in paediatric renal transplant patients. Transplantation 2011; 91: 1380-1385.
46. van den Heuvel ME, van der Lee JH, Cornelissen EA, et al. Transition to the adult nephrologist does not induce acute renal transplant rejection. Nephrol Dial Transplant 2010; 25: 1662-1667.
47. Harambat J, van Stralen KJ, Schaefer F, et al. Disparities in policies, practices and rates of paediatric kidney transplantation in Europe. Am J Transplant 2013; 13: 2066-2074.
