The Study of the Epidemiology of Pediatric Hypertension Registry (SUPERHERO): Rationale and Methods.

Despite increasing prevalence of hypertension in youth and high adult cardiovascular mortality rates, the long-term consequences of youth-onset hypertension remain unknown. This is due to limitations of prior research such as small sample sizes, reliance on manual record review, and limited analytic methods that did not address major biases. The Study of the Epidemiology of Pediatric Hypertension (SUPERHERO) is a multisite retrospective Registry of youth evaluated by subspecialists for hypertension disorders. Sites obtain harmonized electronic health record data using standardized biomedical informatics scripts validated with randomized manual record review. Inclusion criteria are index visit for International Classification of Diseases Diagnostic Codes, 10th Revision (ICD-10 code)-defined hypertension disorder ≥January 1, 2015 and age <19 years. We exclude patients with ICD-10 code-defined pregnancy, kidney failure on dialysis, or kidney transplantation. Data include demographics, anthropomorphics, U.S. Census Bureau tract, histories, blood pressure, ICD-10 codes, medications, laboratory and imaging results, and ambulatory blood pressure. SUPERHERO leverages expertise in epidemiology, statistics, clinical care, and biomedical informatics to create the largest and most diverse registry of youth with newly diagnosed hypertension disorders. SUPERHERO's goals are to (i) reduce CVD burden across the life course and (ii) establish gold-standard biomedical informatics methods for youth with hypertension disorders.

Simultaneous kidney and pancreas transplantation in a patient with nail-patella syndrome and insulin-dependent diabetes.

BACKGROUND: Nail-patella syndrome (NPS) is a rare autosomal dominant disorder caused by a mutation in LIM-homeodomain transcription factor 1-beta (LMX1B) and characterized by nail dystrophy, skeletal changes, glaucoma, and kidney disease with up to 30% of patients progressing to kidney failure. Autoimmune diseases, including thyroid disease, have been reported previously in patients with NPS. CASE-DIAGNOSIS/TREATMENT: We report the case of a pediatric patient with NPS with kidney failure, hypothyroidism, and type 1 diabetes mellitus. The patient's pedigree and identification of a kidney specific mutation in LMX1B was a result of whole exome sequencing. Clinical data was obtained from retrospective chart review and included the 1-year post-transplant follow-up period. At 15 years of age, our patient received a simultaneous kidney-pancreas transplantation, from a 3 HLA antigen mismatched deceased donor. The donor was CMV + , EBV - and our patient was CMV - , EBV - at time of transplant. Our patient maintained normal kidney function and euglycemia without insulin therapy at 1 year post-transplant. CONCLUSIONS: The patient's hypothyroidism, diabetes mellitus, and kidney failure may all be related to LMX1B mutation. Further study is needed to clarify the genetic link between these processes. Simultaneous kidney-pancreas transplantation can be used to successfully treat diabetes mellitus and kidney failure in a pediatric patient.

Mitigating Risk Associated With the Transition From Pediatric to Adult Kidney Transplant Care: Strategies to Promote Success.

Young adult kidney transplant recipients experience poorer outcomes. Specifically worse allograft survival has been reported in the United States and worldwide. Pediatric to adult transition-related research has focused predominantly on medication nonadherence. However, the cause of worse graft outcomes in young adults is likely due to a multitude of complex factors. Consensus guidelines were issued to guide pediatric and adult transplant teams during the transition process. To what extent these transition guidelines are utilized and their impact on improving outcomes for young adult patients is unclear. The consensus guidelines serve as a useful resource, but investigation of the potential barriers to putting these transition guidelines into practice is lacking. One must consider the unique needs of medically complex patients, financial disincentives to transition programs, paucity of evidence-based data to support individual aspects of a transition program and their impact on transition success, and absence of strategies to address health care disparities, all of which can have a multiplicative risk for this population. Key transition research is needed to yield evidence-based data to support transition practices that are successful and truly improve outcomes in this high-risk transplant population. It will also allow better stewardship of transplant organs by optimizing outcomes and allograft longevity.

Access to transplantation for persons with intellectual disability: Strategies for nondiscrimination.

Disqualifying patients with intellectual disabilities (ID) from transplantation has received growing attention from the media, state legislatures, the Office of Civil Rights, and recently the National Council on Disability, as well as internationally. Compared with evidence-based criteria used to determine transplant eligibility, the ID criterion remains controversial because of its potential to be discriminatory, subjective, and because its relationship to outcomes is uncertain. Use of ID in determining transplant candidacy may stem partly from perceived worse adherence and outcomes for patients with ID, fear of penalties to transplant centers for poor outcomes, and stigma surrounding the quality of life for people with ID. However, using ID as a contraindication to solid organ transplantation is not evidence-based and reduces equitable access to transplantation, disadvantaging an already vulnerable population. Variability and lack of transparency in referral and evaluation allows for gatekeeping, threatens patient autonomy, limits access to lifesaving treatment, and may be seen as unfair. We examine the benefits and harms of using ID as a transplant eligibility criterion, review current clinical evidence and ethical considerations, and make recommendations for transplant teams and regulatory agencies to ensure fair access to transplant for individuals with ID.

Does MEST-C score predict outcomes in pediatric Henoch-Schönlein purpura nephritis?

BACKGROUND: Children with Henoch-Schönlein purpura nephritis (HSPN) have an increased risk of chronic kidney disease (CKD). Renal biopsy diagnostic of HSPN is graded using the International Study of Kidney Disease in Children criteria, which do not predict outcomes. The 2016 Oxford Classification's MEST-C scoring system predicts outcomes in adults with histologically identical IgA nephropathy, but evidence of its utility in pediatric HSPN is lacking. Our hypothesis was that MEST-C scores predict outcomes in children with HSPN. METHODS: A retrospective cohort analysis of data from 32 children with HSPN who underwent renal biopsy was performed. We used logistic regression and receiver operator characteristic curves to analyze the ability of MEST-C to predict the composite outcome of hypertension (blood pressure ≥ 95% for age/sex/height), CKD (estimated glomerular filtration rate < 90 mL/min/1.73 m2), or proteinuria (urine protein-to-creatinine ratio > 0.2 mg/mg). RESULTS: The median age at diagnosis was 7.9 years (IQR 5.8, 11.7); 56% were male, 19% were Hispanic, and 9% were Black. After a median follow-up of 2.7 years, 38% of patients (n = 12) reached the outcome. S1 score was significantly associated with the outcome (OR 7.9, 95% CI 1.5-42.6). S1 accurately predicted the outcome (area under the curve 0.72, 95% CI 0.55-0.88) with 58.3% sensitivity and 85.0% specificity, indicating a positive predictive value of 70.0% and a negative predictive value of 77.3%. CONCLUSIONS: S1 accurately predicted our composite outcome of hypertension, CKD, and proteinuria in a diverse cohort of U.S. children with HSPN. Further investigation is warranted to validate these findings.

Severe intellectual disability is not a contraindication to kidney transplantation in children.

Renal transplantation in children with ID is controversial. Acceptability of these children as candidates varies between programs. Limited outcome data in pediatric renal TXP recipients with cognitive impairment diminish their access to TXP. A retrospective chart review was performed of all children who underwent renal transplantation between January 1, 2002 and June 30, 2012 (N=72). Patients were divided into two groups, those with ID prior to transplantation (n=10) and those without (non-ID; n=62). Graft survival and BPAR episodes were compared between the two groups using Kaplan-Meier estimates. Graft survival rates at 3 years post-TXP were 100% in the ID group and 80% in the non-ID group (P=.13). Rates of BPAR at 3 years post-TXP were 10% in the ID group and 27% in the non-ID group (P=.29). Graft survival and acute rejection-free survival rates are similar between children with ID and those without. Based on midterm outcomes, there is no apparent contraindication to renal transplantation in pediatric patients with ID. Children with ID should be considered as TXP candidates provided that they have an adequate social support network.

Bortezomib in the treatment of antibody-mediated rejection in pediatric kidney transplant recipients: A multicenter Midwest Pediatric Nephrology Consortium study.

Antibody-mediated rejection leads to allograft loss after kidney transplantation. Bortezomib has been used in adults for the reversal of antibody-mediated rejection; however, pediatric data are limited. This retrospective study was conducted in collaboration with the Midwest Pediatric Nephrology Consortium. Pediatric kidney transplant recipients who received bortezomib for biopsy-proven antibody-mediated rejection between 2008 and 2015 were included. The objective was to characterize the use of bortezomib in pediatric kidney transplant recipients. Thirty-three patients received bortezomib for antibody-mediated rejection at nine pediatric kidney transplant centers. Ninety percent of patients received intravenous immunoglobulin, 78% received plasmapheresis, and 78% received rituximab. After a median follow-up of 15 months, 65% of patients had a functioning graft. The estimated glomerular filtration rate improved or stabilized in 61% and 36% of patients at 3 and 12 months post-bortezomib, respectively. The estimated glomerular filtration rate at diagnosis significantly predicted estimated glomerular filtration rate at 12 months after adjusting for chronic histologic changes (P .001). Fifty-six percent of patients showed an at least 25% reduction in the mean fluorescence intensity of the immune-dominant donor-specific antibody, 1-3 months after the first dose of bortezomib. Non-life-threatening side effects were documented in 21 of 33 patients. Pediatric kidney transplant recipients tolerated bortezomib without life-threatening side effects. Bortezomib may stabilize estimated glomerular filtration rate for 3-6 months in pediatric kidney transplant recipients with antibody-mediated rejection.

Vitamin D in incident nephrotic syndrome: a Midwest Pediatric Nephrology Consortium study.

BACKGROUND: Cross-sectional studies of children with prevalent nephrotic syndrome (NS) have shown 25-vitamin D (25(OH)D) deficiency rates of 20-100 %. Information on 25(OH)D status in incident patients or following remission is limited. This study aimed to assess 25(OH)D status of incident idiopathic NS children at presentation and longitudinally with short-term observation. METHODS: Multicenter longitudinal study of children (2-18 years old) from 14 centers across the Midwest Pediatric Nephrology Consortium with incident idiopathic NS. 25(OH)D levels were assessed at diagnosis and 3 months later. RESULTS: Sixty-one children, median age 5 (3, 11) years, completed baseline visit and 51 completed second visit labs. All 61 (100 %) had 25(OH)D < 20 ng/ml at diagnosis. Twenty-seven (53 %) had 25(OH)D < 20 ng/ml at follow-up. Fourteen (28 %) children were steroid resistant. Univariate analysis showed that children prescribed vitamin D supplements were less likely to have 25(OH)D deficiency at follow-up (OR 0.2, 95 % CI 0.04, 0.6). Steroid response, age, and season did not predict 25(OH)D deficiency. Multivariable linear regression modeling showed higher 25(OH)D levels at follow-up by 13.2 ng/ml (SE 4.6, p < 0.01) in children supplemented with vitamin D. CONCLUSIONS: In this incident idiopathic NS cohort, all children at diagnosis had 25(OH)D deficiency and the majority continued to have a deficiency at 2-4 months. Supplemental vitamin D decreased the odds of 25(OH)D deficiency at follow-up, supporting a role for supplementation in incident NS.

Does allograft failure impact infection risk on peritoneal dialysis: a North American Pediatric Renal Trials and Collaborative Studies Study.

BACKGROUND AND OBJECTIVES: Several adult studies report that patients returning to peritoneal dialysis after allograft failure have increased infection-related morbidity. The impact of allograft failure on infection risk in children is uncertain. We compared peritonitis-free survival between pediatric peritoneal dialysis patients with prior allograft failure and those who were transplant naive. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We studied patients, 2-21 years of age, who initiated peritoneal dialysis from January 1, 1992, to December 31, 2007, in the North American Pediatric Renal Trials and Collaborative Studies registry. Demographic characteristics were compared between transplant naive and allograft failure patients using a chi-squared statistic. Peritonitis-free survival was compared between the two groups using Kaplan-Meier estimates. A Cox regression analysis was performed to adjust for covariates, which impact risk of peritonitis. RESULTS: Of 2829 patients on peritoneal dialysis, 445 had a prior history of allograft failure and 2384 did not (transplant naive). Demographic characteristics including age at dialysis initiation, race, primary renal disease, and era of dialysis initiation were significantly different between the two groups. Peritonitis-free survival was poorer for the allograft failure group. After covariate adjustment, allograft failure showed borderline significance as a factor predictive of peritonitis. CONCLUSIONS: Children initiating peritoneal dialysis after allograft failure may experience a slightly higher infection risk.

Does allograft failure impact school attendance in children? A NAPRTCS study.

BACKGROUND: Studies show that adult dialysis patients with allograft failure have increased mortality and morbidity on dialysis compared to transplant naïve patients. We previously showed comparable mortality risk in pediatric dialysis patients after allograft failure compared to transplant naïve patients; the impact on morbidity is less clear. Specifically, the effect of allograft failure on school attendance in pediatric patients has not previously been studied. METHODS: Using the North American Pediatric Renal Trials and Collaborative Studies database, we compared school attendance between transplant naïve and allograft failure patients from 1 January 1992 to 31 December 2007. School attendance was compared between the two groups at 6 and 12 months after dialysis initiation using a chi-square test. Factors which can potentially impact on school attendance data were evaluated using a multivariate logistic regression analysis. RESULTS: There were 2783 patients who had a follow-up at least 6 months after dialysis initiation and were capable of attending school during the study period. Patients were categorized by transplant history: previous allograft failure (n=576) and transplant naïve (n=2207). At 6 months, full-time school attendance was 67.2% in the allograft failure group and 72.3% in the transplant naïve group (P=0.0164). At 12 months, attendance was 68.6% in the allograft failure group and 72.5% in the transplant naïve group (P=0.103). After covariate adjustment, transplant failure did not impact school attendance at either 6 or 12 months follow-up [hazard ratio (HR) 1.12, confidence interval (CI) 0.91-1.39; HR 0.99, CI 0.78-1.27, respectively]. CONCLUSIONS: Children with failed allografts who return to dialysis have comparable school attendance compared to their transplant naïve dialysis counterparts. These results suggest that transplant failure is not an adverse prognostic factor for quality of life as measured by full-time school attendance.

An unusual case of membranous nephropathy associated with an ovarian tumor.

Secondary membranous nephropathy (MN) associated with malignancy is not uncommon in adults, but it is rare in children. We report a 6-year-old girl who developed nephrotic-range proteinuria following diagnosis of a Sertoli-Leydig ovarian tumor. A renal biopsy was performed, which led to the diagnosis of MN. The patient maintained normal renal function and gradually showed improvement in proteinuria over several months without the use of corticosteroids or angiotensin-converting enzyme inhibitors. Our case highlights the importance of performing screening urinalyses in children with tumors to recognize the presence of clinically significant, but potentially asymptomatic kidney disease.

Mortality risk in children after renal allograft failure: a NAPRTCS study.

Studies have shown that adult dialysis patients with a failed renal allograft face a greater risk of mortality on dialysis compared with transplant-naïve patients. The outcome of children returning to dialysis after allograft failure has not been previously studied. Using the North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) registry, we studied patients aged 2-21 years who initiated dialysis from 1 January 1992 to 31 December 2007. Of a total of 5,006 patients, 1,031 patients had a prior history of allograft failure and 3,975 did not (transplant-naïve). Demographic characteristics, including age at dialysis initiation, race, dialysis modality, primary renal disease, era of dialysis initiation, height Z score, and weight Z score were significantly different between the groups (p < 0.0001). Survival probability between the transplant-naïve and allograft failure groups was not significantly different (94.3% and 93.7% at 3 years respectively, log-rank p = 0.08). After covariate adjustment, allograft failure was not a significant factor contributing to increased mortality risk on dialysis (HR 0.98, CI 0.64-1.50, p = 0.94) based on Cox regression analysis. Children with failed allografts who return to dialysis are not at greater risk of mortality than their transplant-naïve dialysis counterparts.

Idiopathic membranous nephropathy in pediatric patients: presentation, response to therapy, and long-term outcome.

BACKGROUND: Idiopathic membranous nephropathy (IMN) is one of the most common causes of primary nephrotic syndrome in adults. However, it is a relatively rare entity in the pediatric population and there is a paucity of data about the incidence, prognosis, and optimal treatment of IMN in children and adolescents. We conducted this study to evaluate pediatric patients with IMN in order to clarify the presentation, response to therapy, and clinical outcome. METHODS: A retrospective chart review was performed on patients identified with biopsy-proven IMN between 1988-2005. Patients with systemic lupus erythematosus or hepatitis-related lesions were excluded. The following data were tabulated: age, gender, ethnicity, presenting clinical and laboratory findings, proteinuria in a first morning urine specimen, estimated glomerular filtration rate (GFRe), histopathology, type and duration of treatment, and clinical status at final evaluation. RESULTS: 13 cases of IMN were identified out of 460 renal biopsies performed for evaluation of primary kidney disease during the study interval. Mean age was 9.6 +/- 4.6, gender 6 M:7 F, ethnicity 8 W:2 B:3 H. At the initial visit hematuria was present in 9 patients, edema in 5, nephrotic-range proteinuria in 5, and hypertension in 3. Mean urinary protein:creatinine ratio 3.3 +/- 2.5 and all patients had a normal GFRe. Classic glomerular findings of IMN were seen in all renal specimens, with concomitant interstitial changes in 2 cases. Treatment included an angiotensin converting enzyme inhibitor or angiotensin receptor blocker in 11 cases. Most patients were also given immunosuppressive medications - prednisone in 10, a calcineurin inhibitor in 5, and mycophenolate mofetil or azathioprine in 3 patients. At the last follow-up, 42 +/- 35 months after the diagnostic biopsy, 7 children were hypertensive and the urine protein:creatinine ratio was 2.3 +/- 3.1. The mean GFRe was 127 +/- 57 mL/min/m2. Three patients had Chronic Kidney Disease Stage 3, all of whom were also hypertensive. CONCLUSION: IMN is a rare but serious glomerulopathy in pediatrics. We estimate that it accounts for approximately 3% of renal biopsies. Long-term prognosis is guarded because approximately 50% of patients may have evidence of progressive kidney disease.

Cardiac surgery after renal transplantation.

Renal transplantation remains a mainstay of therapy for end-stage renal disease. Cardiac disease has a high prevalence in this patient population. This study reviews the factors and outcomes associated with cardiac surgery in renal transplant recipients. We performed a retrospective review of all patients at our institution with a functioning renal allograft at the time of their cardiac surgical procedure. Between June 1971 and April 2000, 2343 patients underwent renal transplantation at Vanderbilt University Medical Center. Twenty-six patients with a functioning renal allograft subsequently underwent a cardiac procedure requiring cardiopulmonary bypass. There were 11 women and 15 men. Twenty-four patients underwent coronary bypass, one had a double valve replacement, and one had a combined coronary bypass/valve replacement. The interval from renal transplant to heart surgery ranged between 0.6 and 227 months (mean 79.1). Operative mortality was zero but there were two hospital deaths: one due to multisystem organ failure and one due to pulmonary embolism. Six additional patients died late with only one due to heart disease. Four patients required perioperative dialysis, and one of these went on to require permanent dialysis. Two additional patients returned to dialysis late postoperatively. The requirement for acute perioperative dialysis was predicted by preoperative creatinine, hematocrit, and intraoperative urine output. The overall survival is 69 per cent (18 of 26) with a median follow-up of 38 months. The majority of long-term survivors have minimal cardiac symptoms. Standard cardiac surgery procedures can be performed with relative safety in patients with functioning renal allografts. The incidence of perioperative and late development of renal failure requiring dialysis is low. The long-term survival and symptomatic improvement achieved are favorable and warrant continued performance of cardiac surgery in patients with functioning renal allografts.