Urinary sphingolipids in adolescents and young adults with youth-onset diabetes.

BACKGROUND: This study evaluated urinary sphingolipids as a marker of diabetic kidney disease (DKD) in adolescents and young adults with youth-onset type 1 and type 2 diabetes. METHODS: A comprehensive panel of urinary sphingolipids, including sphingomyelin (SM), glucosylceramide (GC), ceramide (Cer), and lactosylceramide (LC) species, was performed in patients with youth-onset diabetes from the SEARCH for Diabetes in Youth cohort. Sphingolipid levels, normalized to urine creatinine, were compared in 57 adolescents and young adults with type 1 diabetes, 59 with type 2 diabetes, and 44 healthy controls. The association of sphingolipids with albumin-to-creatinine (ACR) ratio and estimated glomerular filtration rate (eGFR) was evaluated. RESULTS: The median age (interquartile range [IQR]) of participants was 23.1 years (20.9, 24.9) and the median duration of diabetes was 9.3 (8.5, 10.2) years. Urinary sphingolipid concentrations in patients with and without DKD (ACR ≥ 30 mg/g) were significantly elevated compared to healthy controls. There were no significant differences in sphingolipid levels between participants with type 1 and type 2 diabetes. In multivariable analysis, many sphingolipid species were positively correlated with ACR. Most significant associations were evident for the following species: C18 SM, C24:1 SM, C24:1 GC, and C24:1 Cer (all p < 0.001). Sphingolipid levels were not associated with eGFR. However, several interaction terms (diabetes type*sphingolipid) were significant, indicating diabetes type may modify the association of sphingolipids with eGFR. CONCLUSION: Urinary sphingolipids are elevated in adolescents and young adults with youth-onset diabetes and correlate with ACR. Urinary sphingolipids may therefore represent an early biomarker of DKD.

Improving Clinical Care for Children With CKD: A Report From a National Kidney Foundation Scientific Workshop.

Development of clinical guidelines and recommendations to address the care of pediatric patients with chronic kidney disease (CKD) has rarely included the perspectives of providers from a variety of health care disciplines or the patients and parents themselves. Accordingly, the National Kidney Foundation hosted an in-person, one and a half-day workshop that convened a multidisciplinary group of physicians, allied health care professionals, and pediatric patients with CKD and their parents, with the goal of developing key clinical recommendations regarding best practices for the clinical management of pediatric patients living with CKD. The key clinical recommendations pertained to 5 broad topics: addressing the needs of patients and parents/caregivers; modifying the progression of CKD; clinical management of CKD-mineral and bone disorder and growth retardation; clinical management of anemia, cardiovascular disease, and hypertension; and transition and transfer of pediatric patients to adult nephrology care. This report describes the recommendations generated by the participants who attended the workshop.

Hypertension in Pediatric Solid Organ Transplant Recipients.

PURPOSE OF REVIEW: To review the current literature regarding hypertension (HTN) following pediatric solid organ transplant (SOTx), including definition, prevalence, risk factors, outcomes, and treatment. RECENT FINDINGS: In recent years several new guidelines for the definition, monitoring, and management of pediatric HTN have been published, but with no specific recommendations regarding SOTx recipients. HTN remains highly prevalent, yet underdiagnosed and undertreated in kidney transplant (KTx) recipients, especially when ambulatory blood pressure monitoring (ABPM) is utilized. There are little data regarding its prevalence in other SOTx recipients. HTN in this population is multifactorial and is associated with HTN status prior to Tx, demographic factors (age, sex, and race), weight status, and immunosuppression protocol. HTN is associated with subclinical cardiovascular (CV) end-organ damage, including left ventricular hypertrophy (LVH) and arterial stiffness, yet there are no recent data regarding its long-term outcomes. There are also no updated recommendations regarding the optimal management of HTN in this population. Given its high prevalence and the young age of this population facing years at increased CV risk, post-Tx HTN requires more clinical attention (routine monitoring, frequent application of ABPM, better BP control). Additional research is needed for a better understanding of its long-term outcomes as well as its treatment and treatment goals. Much more research is needed regarding HTN in other pediatric SOTx populations.

Role of hypertension in progression of pediatric CKD.

Hypertension is frequent in children with chronic kidney disease (CKD). Its prevalence varies according to CKD stage and cause. It is relatively uncommon in children with congenital kidney disease, while acquired kidney disease is associated with a higher prevalence of hypertension. Studies in children with CKD utilizing ambulatory blood pressure monitoring also showed a high prevalence of masked hypertension. Uncontrolled and longstanding hypertension in children is associated with progression of CKD. Aggressive treatment of high blood pressure should be an essential part of care to delay CKD progression in children.

Associations of body mass index (BMI) and BMI change with progression of chronic kidney disease in children.

BACKGROUND: Obesity is prevalent among children with chronic kidney disease (CKD) and is associated with cardiovascular disease and reduced quality of life. Its relationship with pediatric CKD progression has not been described. METHODS: We evaluated relationships between both body mass index (BMI) category (normal, overweight, obese) and BMI z-score (BMIz) change on CKD progression among participants of the Chronic Kidney Disease in Children study. Kaplan-Meier survival curves and multivariable parametric failure time models depict the association of baseline BMI category on time to kidney replacement therapy (KRT). Additionally, the annualized percentage change in estimated glomerular filtration rate (eGFR) was modeled against concurrent change in BMIz using multivariable linear regression with generalized estimating equations which allowed for quantification of the effect of BMIz change on annualized eGFR change. RESULTS: Participants had median age of 10.9 years [IQR: 6.5, 14.6], median eGFR of 50 ml/1.73 m2 [IQR: 37, 64] and 63% were male. 160 (27%) of 600 children with non-glomerular and 77 (31%) of 247 children with glomerular CKD progressed to KRT over a median of 5 years [IQR: 2, 8]. Times to KRT were not significantly associated with baseline BMI category. Children with non-glomerular CKD who were obese experienced significant improvement in eGFR (+ 0.62%; 95% CI: + 0.17%, + 1.08%) for every 0.1 standard deviation concurrent decrease in BMI. In participants with glomerular CKD who were obese, BMIz change was not significantly associated with annualized eGFR change. CONCLUSION: Obesity may represent a target of intervention to improve kidney function in children with non-glomerular CKD. A higher resolution version of the Graphical abstract is available as Supplementary information.

A review of ferric citrate clinical studies, and the rationale and design of the Ferric Citrate and Chronic Kidney Disease in Children (FIT4KiD) trial.

Pediatric chronic kidney disease (CKD) is characterized by many co-morbidities, including impaired growth and development, CKD-mineral and bone disorder, anemia, dysregulated iron metabolism, and cardiovascular disease. In pediatric CKD cohorts, higher circulating concentrations of fibroblast growth factor 23 (FGF23) are associated with some of these adverse clinical outcomes, including CKD progression and left ventricular hypertrophy. It is hypothesized that lowering FGF23 levels will reduce the risk of these events and improve clinical outcomes. Reducing FGF23 levels in CKD may be accomplished by targeting two key stimuli of FGF23 production-dietary phosphate absorption and iron deficiency. Ferric citrate is approved for use as an enteral phosphate binder and iron replacement product in adults with CKD. Clinical trials in adult CKD cohorts have also demonstrated that ferric citrate decreases circulating FGF23 concentrations. This review outlines the possible deleterious effects of excess FGF23 in CKD, summarizes data from the adult CKD clinical trials of ferric citrate, and presents the Ferric Citrate and Chronic Kidney Disease in Children (FIT4KiD) study, a randomized, placebo-controlled trial to evaluate the effects of ferric citrate on FGF23 in pediatric patients with CKD stages 3-4 (ClinicalTrials.gov Identifier NCT04741646).

Factors associated with the absence of pharmacological treatment for common modifiable complications in children with chronic kidney disease.

BACKGROUND: Chronic kidney disease (CKD) is associated with many comorbidities requiring complex management. We described treatment patterns for common modifiable CKD complications (high blood pressure, anemia, hyperphosphatemia, and acidosis) according to severity of CKD and examined factors associated with the absence of drug therapy, among participants with a persistent comorbidity, for 1 year in children enrolled in the CKiD study. METHODS: A total of 703 CKiD participants contributed 2849 person-visits over a median 3.5 years of follow-up. Using pairs of annual visits, we examined whether participants with abnormal biomarker levels at the first (index) visit persisted in the abnormal levels 1 year later according to CKD risk stage. Multivariate analyses identified demographic and clinical factors associated with the absence of drug therapy among those with persistent comorbid conditions for 1 year. RESULTS: The overall proportions of person-visits prescribing therapy at 1-year follow-up for treating anemia, acidosis, hyperphosphatemia, and high blood pressure were 54%, 45%, 29%, and 81%, respectively. The frequency of therapy increased with advanced CKD risk stage for all comorbidities; however, 19-23% of participants with acidosis, 24-27% with anemia, and 30-39% with hyperphosphatemia at high-risk stages (E and F) were not prescribed appropriate therapy despite the persistence of abnormal levels of these biomarkers for at least 1 year. The resolution of comorbidities at advanced CKD stages without treatment was unlikely. CONCLUSIONS: Many children with CKD in the CKiD cohort did not receive pharmacological treatment for common and persistent modifiable comorbidities, even in severe CKD risk stages.

Cardiovascular Risk Reduction in High-Risk Pediatric Patients: A Scientific Statement From the American Heart Association.

This scientific statement presents considerations for clinical management regarding the assessment and risk reduction of select pediatric populations at high risk for premature cardiovascular disease, including acquired arteriosclerosis or atherosclerosis. For each topic, the evidence for accelerated acquired coronary artery disease and stroke in childhood and adolescence and the evidence for benefit of interventions in youth will be reviewed. Children and adolescents may be at higher risk for cardiovascular disease because of significant atherosclerotic or arteriosclerotic risk factors, high-risk conditions that promote atherosclerosis, or coronary artery or other cardiac or vascular abnormalities that make the individual more vulnerable to the adverse effects of traditional cardiovascular risk factors. Existing scientific statements and guidelines will be referenced when applicable, and suggestions for risk identification and reduction specific to each setting will be described. This statement is directed toward pediatric cardiologists, primary care providers, and subspecialists who provide clinical care for these young patients. The focus will be on management and justification for management, minimizing information on pathophysiology and epidemiology.

Using Electronic Health Record Data to Rapidly Identify Children with Glomerular Disease for Clinical Research.

BACKGROUND: The rarity of pediatric glomerular disease makes it difficult to identify sufficient numbers of participants for clinical trials. This leaves limited data to guide improvements in care for these patients. METHODS: The authors developed and tested an electronic health record (EHR) algorithm to identify children with glomerular disease. We used EHR data from 231 patients with glomerular disorders at a single center to develop a computerized algorithm comprising diagnosis, kidney biopsy, and transplant procedure codes. The algorithm was tested using PEDSnet, a national network of eight children's hospitals with data on >6.5 million children. Patients with three or more nephrologist encounters (n=55,560) not meeting the computable phenotype definition of glomerular disease were defined as nonglomerular cases. A reviewer blinded to case status used a standardized form to review random samples of cases (n=800) and nonglomerular cases (n=798). RESULTS: The final algorithm consisted of two or more diagnosis codes from a qualifying list or one diagnosis code and a pretransplant biopsy. Performance characteristics among the population with three or more nephrology encounters were sensitivity, 96% (95% CI, 94% to 97%); specificity, 93% (95% CI, 91% to 94%); positive predictive value (PPV), 89% (95% CI, 86% to 91%); negative predictive value, 97% (95% CI, 96% to 98%); and area under the receiver operating characteristics curve, 94% (95% CI, 93% to 95%). Requiring that the sum of nephrotic syndrome diagnosis codes exceed that of glomerulonephritis codes identified children with nephrotic syndrome or biopsy-based minimal change nephropathy, FSGS, or membranous nephropathy, with 94% sensitivity and 92% PPV. The algorithm identified 6657 children with glomerular disease across PEDSnet, ≥50% of whom were seen within 18 months. CONCLUSIONS: The authors developed an EHR-based algorithm and demonstrated that it had excellent classification accuracy across PEDSnet. This tool may enable faster identification of cohorts of pediatric patients with glomerular disease for observational or prospective studies.

Association between BMI changes and mortality risk in children with end-stage renal disease.

BACKGROUND: Few studies have examined how changes in BMI [body mass index] over time associate with risk of adverse outcomes in children receiving renal replacement therapy [RRT]. The objective of this study was to examine the association between annualized changes in BMI and the risk of death in children treated with RRT. METHODS: We performed a retrospective cohort study of 1182 pediatric dialysis and transplant patients in the Pediatric Growth and Development Special Study of the United States Renal Data System. Quintiles of annualized change in BMI z-score (with cutoffs of - 0.50, - 0.13, 0.09, 0.57) were used as the primary predictor, with the middle quintile (- 0.13 to 0.09) serving as the reference category. Cox models were used to examine the association between exposure and death, with time of analysis starting from the second BMI measurement. RESULTS: Median follow-up time to death or censoring was 6 years. Median age was 14.6 years, and 61% of children had a functional graft at cohort entry. There was a U-shaped association between BMI change and mortality risk: a large decline in annualized BMI z-score change (> - 0.50) was associated with an increased risk of death (adjusted hazard ratio [aHR] 1.54 (95% CI 1.17-2.03), p = 0.002). A large increase in annualized BMI z-score change (> 0.57) was also associated with an increased risk of death (aHR 1.44 (95% CI 1.07-1.92), p = 0.02). No interaction was noted between annualized BMI change and initial treatment modality (dialysis or transplant, p = 0.15). CONCLUSIONS: Maintenance of a stable BMI in pediatric patients receiving RRT may be associated with improved survival.

Cardiometabolic Risk Factors, Metabolic Syndrome, and Chronic Kidney Disease Progression in Children.

OBJECTIVE: To estimate the prevalence of metabolic syndrome (MetS) and examine its association with chronic kidney disease progression in children enrolled in the Chronic Kidney Disease in Children study. STUDY DESIGN: MetS was defined as being overweight or obese and having ≥2 cardiometabolic risk factors (CMRFs). Incidence and prevalence of MetS were assessed using pairs of visits approximately 2 years apart. RESULTS: A total of 799 pairs of person-visits (contributed by 472 children) were included in the final analysis. Of these, 70% had a normal body mass index (BMI), 14% were overweight, and 16% were obese. At the first visit, the prevalence of MetS in the overweight group was 40% and in the obese group was 60%. In adjusted models, annual percent estimated glomerular filtration rate decline in those who had normal BMI and incident or persistent multiple CMRFs or those with persistent MetS was -6.33%, -6.46%, and -6.08% (respectively) compared with children who never had multiple CMRFs (-3.38%, P = .048, .045, and .036, respectively). Children with normal BMI and incident multiple CMRFs and those with persistent MetS had approximately twice the odds of fast estimated glomerular filtration rate decline (>10% per year) compared with those without multiple CMRFs and normal BMI. CONCLUSION: Children with chronic kidney disease have a high prevalence of MetS. These children as well as those with normal BMI but multiple CMRFs experience a faster decline in kidney function.

Cardiac MRI assessment in children and young adults with end-stage renal disease
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Assessment of cardiovascular structure and dysfunction is imperative as cardiovascular disease (CVD) is a major cause of morbidity and mortality in pediatric patients with end-stage renal disease (ESRD). Cardiac magnetic resonance allows for accurate measurement of myocardial volumes, global function, and regional deformation (strain). We studied 38 patients aged from 11 to 26 years: 10 on hemodialysis (HD), 10 on peritoneal dialysis (PD), and 18 post renal transplantation (RT). First, we found no difference in the amount of left ventricular hypertrophy among the three cohorts, but we did find uncontrolled hypertension and black race to be independently associated with increased normalized left ventricular mass. We found left ventricular ejection fraction (LVEF) to be significantly higher in patients after RT compared to those on HD. There was no significant difference in peak systolic circumferential strain (Ecc) among the 3 groups, however, 7 of 9 participants with normal LVEF had low Ecc. We also found a strong association between uncontrolled hypertension and reduced Ecc. These findings indicate the presence of subclinical cardiac dysfunction and the importance of proper management of hypertension in pediatric patients with ESRD.
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Kidney outcomes three years after bariatric surgery in severely obese adolescents.

A significant number of severely obese adolescents undergoing bariatric surgery have evidence of early kidney damage. To determine if kidney injury is reversible following bariatric surgery, we investigated renal outcomes in the Teen-Longitudinal Assessment of Bariatric Surgery cohort, a prospective multicenter study of 242 severely obese adolescents undergoing bariatric surgery. Primary outcomes of urine albumin-to-creatinine ratio and cystatin C-based estimated glomerular filtration rate (eGFR) were evaluated preoperatively and up to 3 years following bariatric surgery. At surgery, mean age of participants was 17 years and median body mass index (BMI) was 51 kg/m2. In those with decreased kidney function at baseline (eGFR under 90 mL/min/1.73m2), mean eGFR significantly improved from 76 to 102 mL/min/1.73m2 at three-year follow-up. Similarly, participants with albuminuria (albumin-to-creatinine ratio of 30 mg/g and more) at baseline demonstrated significant improvement following surgery: geometric mean of ACR was 74 mg/g at baseline and decreased to 17 mg/g at three years. Those with normal renal function and no albuminuria at baseline remained stable throughout the study period. Among individuals with a BMI of 40 kg/m2 and more at follow-up, increased BMI was associated with significantly lower eGFR, while no association was observed in those with a BMI under 40 kg/m2. In adjusted analysis, eGFR increased by 3.9 mL/min/1.73m2 for each 10-unit loss of BMI. Early kidney abnormalities improved following bariatric surgery in adolescents with evidence of preoperative kidney disease. Thus, kidney disease should be considered as a selection criteria for bariatric surgery in severely obese adolescents who fail conventional weight management.

Clinical outcomes and survival in pediatric patients initiating chronic dialysis: a report of the NAPRTCS registry.

BACKGROUND: The 2011 annual report of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) registry comprises data on 6482 dialysis patients over the past 20 years of the registry. METHODS: The study compared clinical parameters and patient survival in the first 10 years of the registry (1992-2001) with the last decade of the registry (2002-2011). RESULTS: There was a significant increase in hemodialysis as the initiating dialysis modality in the most recent cohort (42% vs. 36%, p < 0.001). Patients in the later cohort were less likely to have a hemoglobin <10 g/dl [odds ratio (OR) 0.68; confidence interval (CI) 0.58-0.81; p < 0.001] and height z-score <2 standard deviations (SD) below average (OR 0.68, CI 0.59-0.78, p < 0.0001). They were also more likely to have a parathyroid hormone (PTH) level two times above the upper limits of normal (OR 1.39, CI 1.21-1.60, p < 0.0001). Although hypertension was common regardless of era, patients in the 2002-2011 group were less likely to have blood pressure >90th percentile (OR 1.39, CI 1.21-1.60, p < 0.0001), and a significant improvement in survival at 36 months after dialysis initiation was observed in the 2002-2011 cohort compared with the 1992-2001 cohort (95% vs. 90%, respectively). Cardiopulmonary causes were the most common cause of death in both cohorts. Young age, growth deficit, and black race were poor predictors of survival. CONCLUSIONS: The survival of pediatric patients on chronic dialysis has improved over two decades of dialysis registry data, specifically for children <1year.

Masked hypertension and allograft function in pediatric and young adults kidney transplant recipients.

Masked hypertension is a common complication of pediatric kidney transplantation. While office hypertension is known to be associated with worse short- and long-term graft function, the role of masked hypertension in allograft dysfunction is not clear. We conducted a retrospective cross-sectional analysis of 77 consecutive pediatric kidney transplant recipients who had routine 24-h ambulatory blood pressure monitoring with the aims to estimate the prevalence of masked hypertension and examine its association with allograft function. Masked hypertension was defined as a 24-h systolic or diastolic blood pressure load ≥25%. Twenty-nine percent of patients had masked hypertension. Patients with masked hypertension had significantly lower allograft function estimated using the creatinine-based Schwartz-Lyon formula, a cystatin C-based formula, and combined cystatin C and creatinine-based formulas than patients with normal blood pressure (all p values <0.05). In a multivariable analysis, masked hypertension remained independently associated with worse allograft function after adjustment for age, sex, race, time post-transplant, rejection history, antihypertensive treatment, and hemoglobin level. We conclude that in young kidney transplant recipients, masked hypertension is common and is associated with worse allograft function. These results support the case for routine ambulatory blood pressure monitoring as the standard of care in these patients to detect and treat masked hypertension.

Can office blood pressure readings predict masked hypertension?

BACKGROUND: Studies in children with chronic kidney disease indicate a high prevalence of masked hypertension detected by ambulatory blood pressure monitoring (ABPM). However, it is not well known if the frequency of masked hypertension is related to the level of normal casual blood pressure (BP). METHODS/RESULTS: We hypothesized that lower levels of normal casual BP are associated with a lower prevalence of masked hypertension. Data from the chronic kidney disease (CKiD) cohort were analyzed cross-sectionally across multiple visits. The majority of children with normal casual BP also had normal wake and sleep ABP (60 %), even at the highest percentiles of casual BP. The frequency of masked hypertension was lower in children with casual BP ≤25th percentile versus those with casual BP in 26-50th percentile and casual BP in 51-90th percentile during both wake and sleep periods. In children with the lowest normal casual BP levels (≤25th percentile), the frequency of abnormal mean wake or sleep ABP was 2-7 %, and of abnormal BP load was 6-16 %. CONCLUSIONS: These data suggest that masked hypertension is unlikely if the casual BP is found to be in the low normal range.

Assessment and management of hypertension in transplant patients.

Hypertension in renal transplant recipients is common and ranges from 50% to 80% in adult recipients and from 47% to 82% in pediatric recipients. Cardiovascular morbidity and mortality and shortened allograft survival are important consequences of inadequate control of hypertension. In this review, we examine the epidemiology, pathophysiology, and management considerations of post-transplant hypertension. Donor and recipient factors, acute and chronic allograft injury, and immunosuppressive medications may each explain some of the pathophysiology of post-transplant hypertension. As observed in other patient cohorts, renal artery stenosis and adrenal causes of hypertension may be important contributing factors. Notably, BP treatment goals for renal transplant recipients remain an enigma because there are no adequate randomized controlled trials to support a benefit from targeting lower BP levels on graft and patient survival. The potential for drug-drug interactions and altered pharmacokinetics and pharmacodynamics of the different antihypertensive medications need to be carefully considered. To date, no specific antihypertensive medications have been shown to be more effective than others at improving either patient or graft survival. Identifying the underlying pathophysiology and subsequent individualization of treatment goals are important for improving long-term patient and graft outcomes in these patients.

Hypertension in chronic kidney disease: role of ambulatory blood pressure monitoring.

Children with chronic kidney disease have a markedly increased risk of cardiovascular morbidity and children with end stage renal disease have an estimated 30 times greater risk of cardiovascular mortality than the general pediatric population. In adults, the link between hypertension and cardiovascular disease is well-documented but that association has not been so readily apparent in children with chronic kidney disease. This may be in part because the early changes in blood pressure that occur in these patients do not necessarily manifest with changes in casual blood pressure measurements. Ambulatory blood pressure monitoring, with its ability to gather multiple readings both during the normal activities of the day and the night, is felt to be a more veritable measure of blood pressure. Its use in children has been hampered by limited data on normative values and difficulties in blood pressure classification, while its use in adults is ever expanding. However, with an increasing number of studies in children with chronic kidney disease, ambulatory blood pressure has revealed a greater prevalence of abnormal findings in this population and has been shown to better predict cardiovascular risk than current standards. Two large multi-center studies in Europe and North America have revealed even greater utility of ambulatory blood pressure measures in this population. It is hoped that continued use of ambulatory monitoring in children will help overcome some of its perceived limitations while also validating its use in those at high risk of cardiovascular morbidity.

The mortality risk with graft function has decreased among children receiving a first kidney transplant in the United States.

Mortality has decreased in children with end-stage kidney disease. Decreases in mortality during dialysis and improved graft survival contributed to this improvement. However, it is unknown whether rates of death with graft function have also improved. We measured this in first transplant recipients under 21 years of age registered in the US Renal Data System. Cox models were used with a time-dependent renal replacement therapy modality variable to estimate the hazard ratios (HRs) for death with graft function associated with a 1-year increment in the calendar year of transplant. There were 157,201 person-years of observation among 17,468 recipients, with 82.2% of study time during graft function and 17.8% during dialysis after graft failure. There were 2003 deaths (12.7 deaths per 1000 person-years) overall, of which 985 occurred with graft function (7.6 deaths per 1000 person-years) and 1018 occurred during dialysis after graft failure (36.1 deaths per 1000 person-years). Each 1-year increment in calendar year of first transplant was associated with a significantly lower risk of death, both overall observation (HR 0.97 (0.96, 0.98)) and focusing on time with graft function (HR 0.98 (0.97, 0.99)). Living donation was significantly associated with better survival, whereas dialysis after graft failure was associated with a much higher mortality risk (HR 4.85 (4.40, 5.35)) compared with graft function. Thus, the risk of death with graft function has decreased in children receiving a first kidney transplant. Increasing living donation and minimizing dialysis may further improve outcomes.