Learning from serum markers reflecting endothelial activation: longitudinal data in childhood-onset systemic lupus erythematosus.

OBJECTIVES: In childhood-onset SLE (cSLE), patients have an increased risk of premature atherosclerosis. The pathophysiological mechanisms for this premature atherosclerosis are not yet completely understood, but besides traditional risk factors, the endothelium plays a major role. The first aim of this study was to measure levels of SLE-associated markers involved in endothelial cell (EC) function and lipids in a cSLE cohort longitudinally in comparison with healthy controls (HC). Next aim was to correlate these levels with Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and nailfold capillaroscopic patterns. METHODS: Blood serum samples, videocapillaroscopy images and patient characteristics were collected in a multicentre longitudinal cSLE cohort and from age and sex comparable HC. Disease activity was evaluated by SLEDAI. A total of 15 EC markers and six lipids were measured in two longitudinal cSLE samples (minimum interval of 6 months) and in HC. Nailfold videocapillaroscopy images were scored according to the guidelines from the EULAR Study Group on Microcirculation in Rheumatic Diseases. RESULTS: In total, 47 patients with cSLE and 42 HCs were analysed. Median age at diagnosis was 15 years (IQR 12-16 years). Median time between t=1 and t=2 was 14.5 months (IQR 9-24 months). Median SLEDAI was 12 (IQR 6-18) at t=1 and 2 (IQR 1-4) at t=2. Serum levels of angiopoietin-2, CCL2, CXCL10, GAS6, pentraxin-3, thrombomodulin, VCAM-1 and vWF-A2 were elevated in cSLE compared with HC at t=1. While many elevated EC markers at t=1 normalised over time after treatment, several markers remained significantly increased compared with HC (angiopoietin-2, CCL2, CXCL10, GAS6, thrombomodulin and VCAM-1). CONCLUSION: In serum from patients with cSLE different markers of endothelial activation were dysregulated. While most markers normalised during treatment, others remained elevated in a subset of patients, even during low disease activity. These results suggest a role for the dysregulated endothelium in early and later phases of cSLE, possibly also during lower disease activity. TRIAL REGISTRATION NUMBER: NL60885.018.17.

Population Pharmacokinetics of Adalimumab in Juvenile Idiopathic Arthritis Patients: A Retrospective Cohort Study Using Clinical Care Data.

BACKGROUND AND OBJECTIVE: Juvenile idiopathic arthritis (JIA) is a chronic autoimmune disorder that primarily affects the joints in children. Notably, it is known to co-occur with uveitis. Adalimumab, a monoclonal anti-TNF antibody, is effective in treating both conditions. A deeper understanding of the pharmacokinetics (PK) of adalimumab in JIA is crucial to advance in more personalized treatment approaches. The objective of this study is to evaluate the population PK profile of adalimumab in JIA and to explain causes for its variability. MATERIALS AND METHODS: Adalimumab and antidrug antibody concentrations were retrospectively retrieved from the charts of patients with JIA. Initially, five literature-based population PK models of adalimumab were evaluated to assess their ability to describe the observed concentration-time profiles in the JIA cohort. These models included one specifically for the pediatric Crohn's disease population and four derived from studies in adult populations in healthy subjects and rheumatoid arthritis patients. Subsequently, a novel population PK model tailored to the JIA population was developed using NONMEM software. Monte Carlo simulations were then conducted utilizing the final PK model to visualize the concentration-time profile of adalimumab in patients with JIA and the impact of covariates. RESULTS: A cohort of 50 patients with JIA with 78 available adalimumab samples was assessed. The mean age was 11.8 ± 3.9 years, with a median body weight of 49 kg (interquartile range 29.4-59.8 kg). All literature models adequately described the concentration-time profiles in JIA. The best model, which was developed in patients with rheumatoid arthritis during the maintenance phase of treatment, served as a basis for estimating clearance in JIA, resulting in a value of 0.37 L per day per 70 kg. Patient body weight, antidrug antibodies, methotrexate use, CRP level, and comorbidity of uveitis were found to have a significant impact on adalimumab clearance, and these reduced the inter-patient variability from 58.6 to 28.0%. On steady state in the simulated patient population, the mean trough level was 7.4 ± 5.5 mg/L. The two dosing regimens of 20 and 40 mg every other week, based on patients' body weight, resulted in comparable simulated overall drug exposure. CONCLUSIONS: Five literature models effectively described adalimumab PK in this pediatric cohort, highlighting the potential for extrapolating existing models to the pediatric population. The new JIA model confirmed the effect of several known covariates and found a novel association for drug clearance with methotrexate use (lower) and uveitis (higher), which might have clinical relevance for personalized dosing in JIA.

First validation of the childhood lupus low disease activity state (cLLDAS) definition in a real-life longitudinal cSLE cohort.

OBJECTIVES: To validate the childhood lupus low disease activity state (cLLDAS) definition in cSLE by describing differences in time to reach first adult LLDAS (aLLDAS) versus cLLDAS. Secondly, to analyse positive and negative predictors for maintaining cLLDAS for at least 50% of follow-up time (cLLDAS-50) and for the occurrence of damage. METHODS: Prospective longitudinal data from a cSLE cohort were analysed. Used definitions were: aLLDAS according to Franklyn, cLLDAS by cSLE treat-to-target (T2T) Task Force, disease activity score by SLEDAI -2 K and damage by SLICC damage index. RESULTS: Fifty cSLE patients were studied, with a median follow-up of 3.1 years. Each patient reached aLLDAS and cLLDAS at least once. Mean time to reach first aLLDAS/cLLDAS was 8.2/9.0 months, respectively. For 22/42 patients the mean steroid-dose related delay to reach first cLLDAS was 6.2 months. 58% of patients were able to maintain cLLDAS-50. Time to first cLLDAS (OR 0.8, p = 0.013) and higher number of flares (OR 0.374, p = 0.03) were negative predictors to maintain cLLDAS-50. Damage occurred in 34% of patients (23.5% steroid-related), in 64.7% within one year after diagnosis. African/Afro-Caribbean ethnicity, neuropsychiatric involvement and ever use of a biologic were significant predictors for damage. CONCLUSION: Time to reach cLLDAS in cSLE differs from time to (a)LLDAS, which validates the new cLLDAS definition. Attaining cLLDAS-50 was difficult in real-life. This cohort shows the high risk for early damage in cSLE. T2T with earlier focus on steroid-tapering and starting steroid-sparing drugs seems important to prevent (steroid-related) damage in cSLE.

Transient anti-cytokine autoantibodies superimpose the hyperinflammatory response in Kawasaki disease and multisystem inflammatory syndrome in children: a comparative cohort study on correlates of disease.

BACKGROUND: Children with SARS-CoV-2 related Multisystem Inflammatory Syndrome in Children (MIS-C) often present with clinical features that resemble Kawasaki disease (KD). Disease severity in adult COVID-19 is associated to the presence of anti-cytokine autoantibodies (ACAAs) against type I interferons. Similarly, ACAAs may be implicated in KD and MIS-C. Therefore, we explored the immunological response, presence of ACAAs and disease correlates in both disorders. METHODS: Eighteen inflammatory plasma protein levels and seven ACAAs were measured in KD (n = 216) and MIS-C (n = 56) longitudinally by Luminex and/or ELISA. Levels (up to 1 year post-onset) of these proteins were related to clinical data and compared with healthy paediatric controls. FINDINGS: ACAAs were found in both patient groups. The presence of ACAAs lagged behind the inflammatory plasma proteins and peaked in the subacute phase. ACAAs were mostly directed against IFN-γ (>80%) and were partially neutralising at best. KD presented with a higher variety of ACAAs than MIS-C. Increased levels of anti-IL-17A (P = 0·02) and anti-IL-22 (P = 0·01) were inversely associated with ICU admission in MIS-C. Except for CXCL10 in MIS-C (P = 0·002), inflammatory plasma proteins were elevated in both KD and MIS-C. Endothelial angiopoietin-2 levels were associated with coronary artery aneurysms in KD (P = 0·02); and sCD25 (P = 0·009), angiopoietin-2 (P = 0·001), soluble IL-33-receptor (ST2, P = 0·01) and CXCL10 (P = 0·02) with ICU admission in MIS-C. INTERPRETATION: Markers of endothelial activation (E-selectin, angiopoietin-2), and innate and adaptive immune responses (macrophages [CD163, G-CSF], neutrophils [lipocalin-2], and T cells [IFN-γ, CXCL10, IL-6, IL-17]), are upregulated in KD and MIS-C. ACAAs were detected in both diseases and, although only partly neutralising, their transient presence and increased levels in non-ICU patients may suggest a dampening role on inflammation. FUNDING: The Kawasaki study is funded by the Dutch foundation Fonds Kind & Handicap and an anonymous donor. The sponsors had no role in the study design, analysis, or decision for publication.

Pediatric patient engagement in clinical care, research and intervention development: a scoping review.

BACKGROUND: In the last decades, pediatric patient engagement has received growing attention and its importance is increasingly acknowledged. Pediatric patient engagement in health care can be defined as the involvement of children and adolescents in the decision-making of daily clinical care, research and intervention development. Although more attention is paid to pediatric patient engagement, a comprehensive overview of the activities that have been done regarding pediatric patient engagement and the changes over time is lacking. Therefore, the aim of this study is to provide an overview of the literature about pediatric patient engagement. METHODS: The methodological framework of Arksey & O'Malley was used to conduct this scoping review. The bibliographic databases Medline, Embase, and PsycINFO were searched for eligible articles. All retrieved articles were screened by at least two researchers in two steps. Articles were included if they focused on pediatric patient engagement, were carried out in the context of clinical care in pediatrics, and were published as full text original article in English or Dutch. Data (year of publication, country in which the study was conducted, disease group of the participants, setting of pediatric patient engagement, used methods, and age of participants) were extracted, synthesized, and tabulated. RESULTS: A total of 288 articles out of the 10,714 initial hits met the inclusion criteria. Over the years, there has been an increase in the number of studies that engage pediatric patients. Pediatric patients, especially patients with multiple conditions or oncology patients, were most involved in studies in the United States, United Kingdom, and Canada. Pediatric patients were most often asked to express their views on questions from daily clinical care and the individual interview was the most used method. In general, the extent to which pediatric patients are engaged in health care increases with age. DISCUSSION: This scoping review shows that there is an increasing interest in pediatric patient engagement. However, lack of uniformity about the definition of pediatric patient engagement and clear information for clinicians hinders engagement. This overview can inform clinicians and researchers about the different ways in which pediatric patient engagement can be shaped and can guide them to engage pediatric patients meaningfully in their projects.

Including the voice of paediatric patients: Cocreation of an engagement game.

BACKGROUND: Engaging patients in health care, research and policy is essential to improving patient-important health outcomes and the quality of care. Although the importance of patient engagement is increasingly acknowledged, clinicians and researchers still find it difficult to engage patients, especially paediatric patients. To facilitate the engagement of children and adolescents in health care, the aim of this project is to develop an engagement game. METHODS: A user-centred design was used to develop a patient engagement game in three steps: (1) identification of important themes for adolescents regarding their illness, treatment and hospital care, (2) evaluation of the draft version of the game and (3) testing usability in clinical practice. Adolescents (12-18 years) were engaged in all steps of the development process through focus groups, interviews or a workshop. These were audio-recorded, transcribed verbatim and analysed in MAXQDA. RESULTS: (1) The important themes for adolescents (N = 15) were included: visiting the hospital, participating, disease and treatment, social environment, feelings, dealing with staff, acceptation, autonomy, disclosure and chronically ill peers. (2) Then, based on these themes, the engagement game was developed and the draft version was evaluated by 13 adolescents. Based on their feedback, changes were made to the game (e.g., adjusting the images and changing the game rules). (3) Regarding usability, the pilot version was evaluated positively. The game helped adolescents to give their opinion. Based on the feedback of adolescents, some last adjustments (e.g., changing colours and adding a game board) were made, which led to the final version of the game, All Voices Count. CONCLUSIONS: Working together with adolescents, All Voices Count, a patient engagement game was developed. This game provides clinicians with a tool that supports shared decision-making to address adolescents' wishes and needs. PATIENT OR PUBLIC CONTRIBUTION: Paediatric patients, clinicians, researchers, youth panel of Fonds NutsOhra and patient associations (Patient Alliance for Rare and Genetic Diseases, Dutch Childhood Cancer Organization) were involved in all phases of the development of the patient engagement game-from writing the project plan to the final version of the game.

Nailfold capillary scleroderma pattern may be associated with disease damage in childhood-onset systemic lupus erythematosus: important lessons from longitudinal follow-up.

OBJECTIVES: To observe if capillary patterns in childhood-onset SLE (cSLE) change over time and find associations between a capillary scleroderma pattern with disease activity, damage or scleroderma-like features. METHODS: Clinical and (yearly) capillaroscopy data from a longitudinal cohort of patients with cSLE (minimum of four Systemic Lupus International Collaborating Clinics (SLICC) criteria, onset <18 years) were analysed. Disease activity was measured by Systemic Lupus Erythematosus Activity Index (SLEDAI) and disease damage by SLICC Damage Index. A scleroderma pattern was defined according to the 'fast track algorithm' from the European League Against Rheumatism Study Group on Microcirculation in Rheumatic Diseases. An abnormal capillary pattern, not matching a scleroderma pattern, was defined as 'microangiopathy'. RESULTS: Our cohort consisted of 53 patients with cSLE with a median disease onset of 14 years (IQR 12.5-15.5 years), median SLEDAI score at diagnosis was 11 (IQR 8-16), median SLEDAI at follow-up was 2 (IQR 1-6). A scleroderma pattern (ever) was seen in 18.9%, while only 13.2% of patients had a normal capillary pattern. Thirty-three patients had follow-up capillaroscopy of which 21.2% showed changes in type of capillary pattern over time. Type of capillary pattern was not associated with disease activity. Raynaud's phenomenon (ever) was equally distributed among patients with different capillaroscopy patterns (p=0.26). Anti-ribonucleoprotein antibodies (ever) were significantly more detected (Χ2, p=0.016) in the scleroderma pattern subgroup (n=7 of 10, 70%). Already 5 years after disease onset, more than 50% of patients with a scleroderma pattern had SLE-related disease damage (HR 4.5, 95% CI 1.1 to 18.8, p=0.034), but they did not develop clinical features of systemic sclerosis at follow-up. Number of detected fingers with a scleroderma pattern was similar between cSLE, juvenile systemic sclerosis and juvenile undifferentiated connective tissue disease. CONCLUSION: This longitudinal study shows that the majority of capillary patterns in cSLE are abnormal and they can change over time. Irrespective of disease activity, a capillary scleroderma pattern in cSLE may be associated with higher risk of SLE-related disease damage.

A randomized clinical trial indicates that levamisole increases the time to relapse in children with steroid-sensitive idiopathic nephrotic syndrome.

Levamisole has been considered the least toxic and least expensive steroid-sparing drug for preventing relapses of steroid-sensitive idiopathic nephrotic syndrome (SSINS). However, evidence for this is limited as previous randomized clinical trials were found to have methodological limitations. Therefore, we conducted an international multicenter, placebo-controlled, double-blind, randomized clinical trial to reassess its usefulness in prevention of relapses in children with SSINS. The efficacy and safety of one year of levamisole treatment in children with SSINS and frequent relapses were evaluated. The primary analysis cohort consisted of 99 patients from 6 countries. Between 100 days and 12 months after the start of study medication, the time to relapse (primary endpoint) was significantly increased in the levamisole compared to the placebo group (hazard ratio 0.22 [95% confidence interval 0.11-0.43]). Significantly, after 12 months of treatment, six percent of placebo patients versus 26 percent of levamisole patients were still in remission. During this period, the most frequent serious adverse event (four of 50 patients) possibly related to levamisole was asymptomatic moderate neutropenia, which was reversible spontaneously or after treatment discontinuation. Thus, in children with SSINS and frequent relapses, levamisole prolonged the time to relapse and also prevented recurrence during one year of treatment compared to prednisone alone. However, regular blood controls are necessary for safety issues.

Prevention of steroid-induced low bone mineral density in children with renal diseases: a systematic review.

BACKGROUND: Children with renal diseases who are treated with glucocorticoids are at increased risk of developing osteoporosis and fractures. However, there is no common strategy for prevention of corticosteroid-induced osteoporosis. The present systematic review was performed to determine whether prevention of bone loss by calcium (Ca), vitamin D (vit D) and/or bisphosphonates is justified, safe and efficacious in children treated with steroids for various renal diseases. DATA SOURCES: Medline, Embase, Central were searched from 1961 up to 2012. Randomized controlled trials (RCTs) and observational studies concerning children ≤18 years with renal diseases requiring steroids were included. RESULTS: The search strategy retrieved 2482 studies. Four RCTs including 166 patients and one observational study including 100 children met our eligibility criteria. One RCT and the observational study concerned treatment with Ca/vit D, one RCT with bisphosphonates and two RCTs with a combination of both therapies. All described a significant improvement in bone mineral density (BMD) in the treatment group compared with the control group. CONCLUSIONS:  Ca combined with vit D is recommended to prevent bone disease in children with renal diseases treated with steroids. Because of side effects, bisphosphonates should be reserved for the treatment of severe osteoporosis when Ca and/or vit D supplementation has failed.

Cardiac disease in young adult patients with end-stage renal disease since childhood: a Dutch cohort study.

BACKGROUND: Cardiovascular disease is the most important cause of death in patients with pediatric end-stage renal disease (ESRD). Yet, few data exist on cardiac function in these patients. We assessed the extent of cardiac abnormality and analyzed its association with potential determinants in young adult patients with pediatric ESRD in a long-term follow-up study. METHODS: All Dutch living adult patients with ESRD onset at age of 0 to 14 years between 1972 and 1992 were invited for echocardiography and blood pressure assessment. Special attention was paid to evidence of left ventricular hypertrophy (LVH), diastolic dysfunction, and aortic valve calcification. We collected data on determinants by review of all medical charts. RESULTS: Of all the 187 living patients, 140 participated in the study. Of those, 110 patients had received a transplant and 30 patients were on dialysis. Mean age was 29.2 (20.7 to 41.8) years. Left ventricular mass index (LVMI) exceeded 150 g/m2 in 47% of all male patients and 120 g/m2 in 39% of all female patients, both consistent with LVH. Diastolic dysfunction, defined as an early over atrial transmitral blood flow velocity (E/A ratio) <1, was found in 18 (13%) patients; 27 (19%) had aortic valve calcification. Multiple regression analysis revealed the following: a high LVMI was associated with a current high blood pressure (beta=0.46, P < 0.001) and male gender (beta=0.21, P=0.009), a low E/A ratio with aging (beta=-0.28, P < 0.001) and a glomerular filtration rate (GFR) <25 mL/min/1.73 m2 (beta=-0.29, P < 0.001), and aortic valve calcification with prolonged peritoneal dialysis (beta=0.36, P < 0.001). CONCLUSION: Young adult patients with pediatric ESRD are at risk for LVH caused by hypertension and for aortic valve calcification. Diastolic function decreases with age and is enhanced by a current low GFR. Prolonged peritoneal dialysis may enhance aortic valve calcification.

Quality of life in adults with end-stage renal disease since childhood is only partially impaired.

BACKGROUND: Little is known about the quality of life of adults with end-stage renal disease (ESRD) since childhood. In a long-term follow-up study, we assessed quality of life in these patients and compared their outcomes with those in the general population and in dialysis patients with adult-onset of ESRD. METHODS: All Dutch adult patients with onset of ESRD at age 0-14 years between 1972 and 1992 were asked to complete the RAND-36 questionnaire. We obtained clinical information by reviewing all available medical charts, and by current history. Patient scores were compared with those of age-matched healthy controls and with those of patients with adult onset of dialysis, of whom data were derived from a national study on the adequacy of dialysis (NECOSAD-2). RESULTS: We obtained a complete RAND-36 score in 131 of 187 surviving patients. Clinical characteristics of participants and non-participants were similar. Compared with the general population, we found a higher prevalence of impaired quality of life in dialysis patients in the following domains: physical functioning, role limitations due to physical health, social functioning (SF), general health perception (GH) and physical component summary. In other domains, impaired quality of life was equally or less prevalent (mental component summary). In transplanted patients, only impaired GH and SF were more prevalent. In dialysis patients with adult ESRD onset, impaired quality of life was more prevalent than in the general population in all domains, except in emotional role limitations. CONCLUSIONS: Dialysis patients with paediatric ESRD have an impaired physical quality of life, but in contrast to dialysis patients with adult ESRD onset, they have a normal mental quality of life.

Severe bone disease and low bone mineral density after juvenile renal failure.

BACKGROUND: Little is known about the late effects of juvenile end-stage renal disease (ESRD) on bone integrity. To establish clinical manifestations of metabolic bone disease and bone mineral density (BMD) in young adult patients with juvenile ESRD, we performed a long-term outcome study. METHODS: A cohort was formed of all Dutch patients with onset of ESRD between 1972 and 1992 at age 0 to 14 years, born before 1979. Data were collected by review of medical charts, current history, physical examination, and performing dual energy x-ray absorptiometry (DEXA) of the lumbar spine and the femoral neck. RESULTS: Clinical information was retrieved in 247 out of 249 patients. Of all of these patients, 61.4% had severe growth retardation (<-2 SD), 36.8% had clinical symptoms of bone disease, and 17.8% were disabled by bone disease. Growth retardation and clinical bone disease were associated with a long duration of dialysis. DEXA was performed in 140 out of 187 living patients. Mean BMD +/- SD corrected for gender and age (Z score) of the lumbar spine was -2.12 +/- 1.4 and of the femoral neck was -1.77 +/- 1.4. A low lean body mass was associated with a low lumbar spine and a low femoral neck BMD; male gender, physical inactivity and aseptic bone necrosis were associated with a low lumbar spine BMD. CONCLUSION: Bone disease is a major clinical problem in young adults with pediatric ESRD. Further follow-up is needed to establish the impact of the low bone mineral densities found in these patients.

Increased arterial stiffness in young adults with end-stage renal disease since childhood.

Increased arterial stiffness is a risk factor for mortality in adults over 40 yr of age with end-stage renal disease (ESRD). As no data exist on vascular changes in young adults with ESRD since childhood, a long-term outcome study was performed. All living Dutch adult patients with onset of ESRD between 1972 and 1992 at age 0 to 14 yr were invited for carotid artery and cardiac ultrasound and BP measurements. Data on clinical characteristics were collected by review of all medical charts. Carotid ultrasound data were compared with those of 48 age-matched and gender-matched healthy controls. Carotid artery and cardiac ultrasound was performed in 130 out of 187 eligible patients. Mean age was 29.0 (20.7 to 40.6) yr. Compared with controls, patients had a similar intima media thickness but a reduced mean arterial wall distensibility DC (40.0 versus 45.0 kPa(-1). 10(-3); 95% CI, -9.1 to -0.8; P < 0.001), an increased stiffness parameter beta (4.2 versus 3.8; 95% CI, 0.05 to 0.68; P = 0.02), an increased elastic incremental modulus E(inc) (0.35 versus 0.27 kPa. 10(3); 95% CI, 0.02 to 0.12; P < 0.001). Multiple regression analyses in all subjects revealed that ESRD was associated with an increase in beta and E(inc). Arterial wall properties of patients currently on dialysis and transplanted patients were comparable. In all patients, current systolic hypertension was associated with increased E(inc) and decreased DC. In conclusion, carotid arterial wall stiffness is increased in young adult patients with pediatric ESRD. Hypertension is a main determinant and might be a target for treatment of these potentially lethal arterial wall changes.

Mortality and causes of death of end-stage renal disease in children: a Dutch cohort study.

BACKGROUND: To establish mortality rates, causes of death, and determinants of mortality in children with end-stage renal disease (ESRD), we performed a national long-term follow up study. METHODS: Mortality rate was determined in all Dutch patients with onset of ESRD at ages 0 to 14 years in the period between 1972 and 1992. Causes of death and mortality determinants were investigated in all patients of this cohort who were born before 1979. Data were derived from the Dutch Registry for patients on renal replacement therapy (RRT), medical charts and National Health Database. RESULTS: Of all 381 patients 85 had died. The overall mortality rate (MR) was 1.57/100 patient-years, and the standardized mortality rate (SMR) was 31.0. The MR for patients 0 to 5 and 6 to 10 years old at onset of ESRD decreased from, respectively, 7.0 (range 0-14.9) to 3.9 (1.2-6.7) and 4.3 (1.1-7.5) to 1.6 (0.3-2.8) between the periods 1972-1981 and 1982-1992. The mortality hazard ratio of relatively long standing dialysis and of long standing hypertension were, respectively, 7.2 (4.4-11.8) and 3.1 (2.1-4.6), of cyclosporine-introduction in transplanted patients 0.3 (0.1-0.4). Overall cerebrovascular accidents (24%) and infections (21%) were the most common causes of death; after 10 years of RRT cardiac death (7/21) was most prevalent. Cardiovascular death was most prominent in dialysis as well as transplanted patients. CONCLUSION: Survival in children with ESRD has increased over the last 20 years, but the SMR remains high. Early transplantation and a more vigorous approach toward hypertension and infection may be mandatory in order to further reduce mortality.