A Comprehensive Mixed-Method Approach to Characterize the Source of Diurnal Tacrolimus Exposure Variability in Children: Systematic Review, Meta-analysis, and Application to an Existing Data Set.

Tacrolimus is widely reported to display diurnal variation in pharmacokinetic parameters with twice-daily dosing. However, the contribution of chronopharmacokinetics versus food intake is unclear, with even less evidence in the pediatric population. The objectives of this study were to summarize the existing literature by meta-analysis and evaluate the impact of food composition on 24-hour pharmacokinetics in pediatric kidney transplant recipients. For the meta-analysis, 10 studies involving 253 individuals were included. The pooled effect sizes demonstrated significant differences in area under the concentration-time curve from time 0 to 12 hours (standardized mean difference [SMD], 0.27; 95% confidence interval [CI], 0.03-0.52) and maximum concentration (SMD, 0.75; 95% CI, 0.35-1.15) between morning and evening dose administration. However, there was significant between-study heterogeneity that was explained by food exposure. The effect size for minimum concentration was not significantly different overall (SMD, -0.09; 95% CI, -0.27 to 0.09) or across the food exposure subgroups. A 2-compartment model with a lag time, linear clearance, and first-order absorption best characterized the tacrolimus pharmacokinetics in pediatric participants. As expected, adding the time of administration and food composition covariates reduced the unexplained within-subject variability for the first-order absorption rate constant, but only caloric composition significantly reduced variability for lag time. The available data suggest food intake is the major driver of diurnal variation in tacrolimus exposure, but the associated changes are not reflected by trough concentrations alone.

COVID-19 in pediatric kidney transplantation: a follow-up report of the Improving Renal Outcomes Collaborative.

BACKGROUND: We report follow-up data from an ongoing prospective cohort study of COVID-19 in pediatric kidney transplantation through the Improving Renal Outcomes Collaborative (IROC). METHODS: Patient-level data from the IROC registry were combined with testing, indication, and outcomes data collected to describe the epidemiology of COVID testing, treatment, and clinical outcomes; determine the incidence of a positive COVID-19 test; describe rates of COVID-19 testing; and assess for clinical predictors of a positive COVID-19 test. RESULTS: From September 2020 to February 2021, 21 centers that care for 2690 patients submitted data from 648 COVID-19 tests on 465 patients. Most patients required supportive care only and were treated as outpatients, 16% experienced inpatient care, and 5% experienced intensive care. Allograft complications were rare, with acute kidney injury most common (7%). There was 1 case of respiratory failure and 1 death attributed to COVID-19. Twelve centers that care for 1730 patients submitted complete testing data on 351 patients. The incidence of COVID-19 among patients at these centers was 4%, whereas the incidence among tested patients was 19%. Risk factors to predict a positive COVID-19 test included age > 12 years, symptoms consistent with COVID-19, and close contact with a confirmed case of COVID-19. CONCLUSIONS: Despite the increase in testing and positive tests over this study period, the incidence of allograft loss or death related to COVID-19 remained extremely low, with allograft loss or death each occurring in < 1% of COVID-19-positive patients and in less than < 0.1% of all transplant patients within the IROC cohort. A higher resolution version of the Graphical abstract is available as Supplementary information.

Timing of procedural interventions in childhood renovascular hypertension.

BACKGROUND: Renovascular hypertension (RVHTN) is a rare, often complex condition due to multiple etiologies including congenital stenoses, vasculitides, and fibromuscular dysplasia. Among children with RVHTN who require multiple and escalating medications to control blood pressure, the optimal timing of a procedural intervention involves a balance of numerous factors. CASE-DIAGNOSIS/TREATMENT: In this presentation of a 1-month-old girl with RVHTN, the treating medical team had to consider multiple factors in the initial management and timing of interventions to treat her underlying cause of RVHTN, including concerns for kidney health, degree of hypertension, age and size of the patient, and potential methods of procedural intervention. Initially, she was treated conservatively until concern for poor renal growth arose and a durable surgical intervention was thought feasible and safe. CONCLUSION: The evidence regarding the timing of non-medical interventions in pediatric RVHTN is limited. Considerations should include patient age, size, disease severity, comorbid conditions, and degree of medical management required to maintain safe blood pressures that allow for growth and reverse cardiac damage. The optimal interventions have not been evaluated by controlled trials and should be decided on a case-by-case basis with consideration of center expertise and family preferences.

COVID-19 in pediatric kidney transplantation: The Improving Renal Outcomes Collaborative.

There are limited data on the impact of COVID-19 in children with a kidney transplant (KT). We conducted a prospective cohort study through the Improving Renal Outcomes Collaborative (IROC) to collect clinical outcome data about COVID-19 in pediatric KT patients. Twenty-two IROC centers that care for 2732 patients submitted testing and outcomes data for 281 patients tested for SARS-CoV-2 by PCR. Testing indications included symptoms and/or potential exposures to COVID-19 (N = 134, 47.7%) and/or testing per hospital policy (N = 154, 54.8%). Overall, 24 (8.5%) patients tested positive, of which 15 (63%) were symptomatic. Of the COVID-19-positive patients, 16 were managed as outpatients, six received non-ICU inpatient care and two were admitted to the ICU. There were no episodes of respiratory failure, allograft loss, or death associated with COVID-19. To estimate incidence, subanalysis was performed for 13 centers that care for 1686 patients that submitted all negative and positive COVID-19 results. Of the 229 tested patients at these 13 centers, 10 (5 asymptomatic) patients tested positive, yielding an overall incidence of 0.6% and an incidence among tested patients of 4.4%. Pediatric KT patients in the United States had a low estimated incidence of COVID-19 disease and excellent short-term outcomes.

The Improving Renal Outcomes Collaborative: Blood Pressure Measurement in Transplant Recipients.

BACKGROUND AND OBJECTIVES: Hypertension is highly prevalent in pediatric kidney transplant recipients and contributes to cardiovascular death and graft loss. Improper blood pressure (BP) measurement limits the ability to control hypertension in this population. Here, we report multicenter efforts from the Improving Renal Outcomes Collaborative (IROC) to standardize and improve appropriate BP measurement in transplant patients. METHODS: Seventeen centers participated in structured quality improvement activities facilitated by IROC, including formal training in quality improvement methods. The primary outcome measure was the proportion of transplant clinic visits with appropriate BP measurement according to published guidelines. Prospective data were analyzed over a 12-week pre-intervention period and a 20-week active intervention period for each center and then aggregated as of the program-specific start date. We used control charts to quantify improvements across IROC centers. We applied thematic analysis to identify patterns and common themes of successful interventions. RESULTS: We analyzed data from 5392 clinic visits. At baseline, BP was measured and documented appropriately at 11% of visits. Center-specific interventions for improving BP measurement included educating clinic staff, assigning specific team member roles, and creating BP tracking tools and alerts. Appropriate BP measurement improved throughout the 20-week active intervention period to 78% of visits. CONCLUSIONS: We standardized appropriate BP measurement across 17 pediatric transplant centers using the infrastructure of the IROC learning health system and substantially improved the rate of appropriate measurement over 20 weeks. Accurate BP assessment will allow further interventions to reduce complications of hypertension in pediatric kidney transplant recipients.

Surgical management of pediatric renin-mediated hypertension secondary to renal artery occlusive disease and abdominal aortic coarctation.

BACKGROUND: Renovascular hypertension (RVH) associated with renal artery and abdominal aortic narrowings is the third most common cause of pediatric hypertension. Untreated children may experience major cardiopulmonary complications, stroke, renal failure, and death. The impetus of this study was to describe the increasingly complex surgical practice for such patients with an emphasis on anatomic phenotype and contemporary outcomes after surgical management as a means of identifying those factors responsible for persistent or recurrent hypertension necessitating reoperation. METHODS: A retrospective analysis was performed of consecutive pediatric patients with RVH undergoing open surgical procedures at the University of Michigan from 1991 to 2017. Anatomic phenotype and patient risk factors were analyzed to predict outcomes of blood pressure control and the need for secondary operations using ordered and binomial logistic multinomial regression models, respectively. RESULTS: There were 169 children (76 girls, 93 boys) who underwent primary index operations at a median age of 8.3 years; 31 children (18%) had neurofibromatosis type 1, 76 (45%) had abdominal aortic coarctations, and 28 (17%) had a single functioning kidney. Before treatment at the University of Michigan, 51 children experienced failed previous open operations (15) or endovascular interventions (36) for RVH at other institutions. Primary surgical interventions (342) included main renal artery (136) and segmental renal artery (10) aortic reimplantation, renal artery bypass (55), segmental renal artery embolization (10), renal artery patch angioplasty (8), resection with reanastomosis (4), and partial or total nephrectomy (25). Non-renal artery procedures included patch aortoplasty (32), aortoaortic bypass (32), and splanchnic arterial revascularization (30). Nine patients required reoperation in the early postoperative period. During a mean follow-up of 49 months, secondary interventions were required in 35 children (21%), including both open surgical (37) and endovascular (14) interventions. Remedial intervention to preserve primary renal artery patency or a nephrectomy if such was impossible was required in 22 children (13%). The remaining secondary procedures were performed to treat previously untreated disease that became clinically evident during follow-up. Age at operation and abdominal aortic coarctation were independent predictors for reoperation. The overall experience revealed hypertension to be cured in 74 children (44%), improved in 78 (46%), and unchanged in 17 (10%). Children undergoing remedial operations were less likely (33%) to be cured of hypertension. There was no perioperative death or renal insufficiency requiring dialysis after either primary or secondary interventions. CONCLUSIONS: Contemporary surgical treatment of pediatric RVH provides a sustainable overall benefit to 90% of children. Interventions in the very young (<3 years) and concurrent abdominal aortic coarctation increase the likelihood of reoperation. Patients undergoing remedial surgery after earlier operative failures are less likely to be cured of hypertension. Judicious postoperative surveillance is imperative in children surgically treated for RVH.

Podocyte Depletion in Thin GBM and Alport Syndrome.

The proximate genetic cause of both Thin GBM and Alport Syndrome (AS) is abnormal α3, 4 and 5 collagen IV chains resulting in abnormal glomerular basement membrane (GBM) structure/function. We previously reported that podocyte detachment rate measured in urine is increased in AS, suggesting that podocyte depletion could play a role in causing progressive loss of kidney function. To test this hypothesis podometric parameters were measured in 26 kidney biopsies from 21 patients aged 2-17 years with a clinic-pathologic diagnosis including both classic Alport Syndrome with thin and thick GBM segments and lamellated lamina densa [n = 15] and Thin GBM cases [n = 6]. Protocol biopsies from deceased donor kidneys were used as age-matched controls. Podocyte depletion was present in AS biopsies prior to detectable histologic abnormalities. No abnormality was detected by light microscopy at <30% podocyte depletion, minor pathologic changes (mesangial expansion and adhesions to Bowman's capsule) were present at 30-50% podocyte depletion, and FSGS was progressively present above 50% podocyte depletion. eGFR did not change measurably until >70% podocyte depletion. Low level proteinuria was an early event at about 25% podocyte depletion and increased in proportion to podocyte depletion. These quantitative data parallel those from model systems where podocyte depletion is the causative event. This result supports a hypothesis that in AS podocyte adherence to the GBM is defective resulting in accelerated podocyte detachment causing progressive podocyte depletion leading to FSGS-like pathologic changes and eventual End Stage Kidney Disease. Early intervention to reduce podocyte depletion is projected to prolong kidney survival in AS.

Remedial operations for failed endovascular therapy of 32 renal artery stenoses in 24 children.

BACKGROUND: Percutaneous transluminal angioplasty (PTA) for the treatment of pediatric renovascular hypertension (RVH) in contemporary practice is accompanied with ill-defined complications. This study examines the mode of pediatric renal PTA failures and the results of their surgical management. METHODS: Twenty-four children underwent remedial operations at the University of Michigan from 1996 to 2014 for failures of renal PTA. Their clinical courses were retrospectively reviewed and results analyzed. RESULTS: Renal PTA of 32 arteries, including 13 with stenting, was performed for severe RVH in 12 boys and 12 girls, having a mean age of 9.3 years. Developmental ostial stenoses affected 22 children. PTA failures included: 27 restenoses and five thromboses. Remedial operations included: 13 renal artery-aortic reimplantations, one segmental renal artery-main renal artery reimplantation, ten aortorenal bypasses, one arterioplasty, one iliorenal bypass, and six nephrectomies for unreconstructable arteries; the latter all in children younger than 10 years. Follow-up averaged 2.1 years. Postoperatively, hypertension was cured, improved, or unchanged in 25, 54, and 21 %, respectively. There was no perioperative renal failure or mortality. CONCLUSIONS: Renal PTA for the treatment of pediatric RVH due to ostial disease may be complicated by failures requiring complex remedial operations or nephrectomy, the latter usually affecting younger children.

Pediatric Hypertension Specialists' Perspectives About Adolescent Hypertension Management: Implications for Primary Care Providers.

BACKGROUND: The current specialty-centric hypertension paradigm is unsustainable given the high prevalence of primary hypertension in adolescents. OBJECTIVE: To describe specialists' perspectives on referral and comanagement for adolescents with hypertension. METHODS: Cross-sectional mailed survey of a national sample of 397 pediatric cardiologists and 389 pediatric nephrologists, conducted January to May 2014. RESULTS: Response rate was 61%. Both specialties agreed that primary care providers can make the hypertension diagnosis, try lifestyle changes, and comanage monitoring of patient blood pressure control and medication side effects, but they felt antihypertensive medication use should mainly occur in the specialty setting. CONCLUSIONS: Our study suggests specialist support for changing the hypertension paradigm to encourage primary care providers, in collaboration with specialists, to diagnose hypertension, initiate lifestyle changes, and monitor progress and side effects. Future work should focus on supporting primary care physician comanagement of adolescents with hypertension.

Validation of the KDIGO acute kidney injury criteria in a pediatric critical care population.

PURPOSE: Acute kidney injury (AKI) occurs commonly in critically ill children and has been associated with increased mortality of up to 50 %. The Kidney Disease: Improving Global Outcomes (KDIGO) AKI working group has proposed a standardized definition of AKI. Utilizing routinely available clinical data, we evaluated the KDIGO AKI criteria and the relationship of AKI with relevant outcomes in a single center tertiary pediatric intensive care (PICU) and cardiac intensive care unit (CICU) population. METHODS: The University of Michigan Pediatric Critical Care Database was probed for all discharges from the pediatric intensive care and cardiac intensive care units between July 2011 and October 2013 (N = 4,645). The KDIGO serum creatinine (SCr)-based criteria staged AKI with the modification that a minimum SCr of greater than 0.5 mg/dL was required to be classified as AKI. Exclusion: end-stage renal disease, new renal transplant, missing PRISM III data, or no measured Cr during intensive care unit (ICU) admission (N = 1,636). RESULTS: AKI occurred in 737 (24.5 %, stage 1 = 193, stage 2 = 189, and stage 3 = 355) of 3,009 discharges (PICU N = 1,870, CICU N = 1,139) that included 2,415 patients. In multivariate analysis AKI was associated with increased ICU length of stay (LOS) in hours (stage I ß = 42.2, p = 0.024, II ß = 74.1, p = 0.003, III ß = 215.8, p < 0.001). Multivariate analysis showed that AKI was associated with increased odds of ICU mortality (OR 3.4, 95 % CI 2.0-6.0) and increased length of mechanical ventilation among those requiring mechanical ventilation (ß = 2.3 days, p < 0.001). CONCLUSIONS: Using the KDIGO criteria to define AKI, we observed a high prevalence of AKI among critically ill children. Worsening stages of AKI were associated with increased ICU LOS, and AKI was independently associated with prolonged mechanical ventilation and increased mortality. The KDIGO criteria describe clinically relevant AKI in a broad pediatric critical care population.

Gaining the Patient Reported Outcomes Measurement Information System (PROMIS) perspective in chronic kidney disease: a Midwest Pediatric Nephrology Consortium study.

BACKGROUND AND OBJECTIVES: Chronic kidney disease is a persistent chronic health condition commonly seen in pediatric nephrology programs. Our study aims to evaluate the sensitivity of the Patient Reported Outcomes Measurement Information System (PROMIS) pediatric instrument to indicators of disease severity and activity in pediatric chronic kidney disease. METHODS: This cross sectional study included 233 children 8-17 years old, with chronic kidney disease from 16 participating institutions in North America. Disease activity indicators, including hospitalization in the previous 6 months, edema, and number of medications consumed daily, as well as disease severity indicators of kidney function and coexisting medical conditions were captured. PROMIS domains, including depression, anxiety, social-peer relationships, pain interference, fatigue, mobility, and upper extremity function, were administered via web-based questionnaires. Absolute effect sizes (AES) were generated to demonstrate the impact of disease on domain scores. Four children were excluded because of missing glomerular filtration rate (GFR) estimations. RESULTS: Of the 229 children included in the final analysis, 221 completed the entire PROMIS questionnaire. Unadjusted PROMIS domains were responsive to chronic kidney disease activity indicators and number of coexisting conditions. PROMIS domain scores were worse in the presence of recent hospitalizations (depression AES 0.33, anxiety AES 0.42, pain interference AES 0.46, fatigue AES 0.50, mobility AES 0.49), edema (depression AES 0.50, anxiety AES 0.60, pain interference AES 0.77, mobility AES 0.54) and coexisting medical conditions (social peer-relationships AES 0.66, fatigue AES 0.83, mobility AES 0.60, upper extremity function AES 0.48). CONCLUSIONS: The PROMIS pediatric domains of depression, anxiety, social-peer relationships, pain interference, and mobility were sensitive to the clinical status of children with chronic kidney disease in this multi-center cross sectional study. We demonstrated that a number of important clinical characteristics including recent history of hospitalization and edema, affected patient perceptions of depression, anxiety, pain interference, fatigue and mobility. The PROMIS instruments provide a potentially valuable tool to study the impact of chronic kidney disease. Additional studies will be required to assess responsiveness in PROMIS score with changes in disease status over time.

Incidence of nonconfounded post-computed tomography acute kidney injury in hospitalized patients with stable renal function receiving intravenous iodinated contrast material.

OBJECTIVE: The purpose of our investigation was to determine the frequency of proximate acute and chronic confounding risk factors for acute kidney injury (AKI) in a cohort of adult hospitalized patients with stable renal function who developed AKI following an intravenous (IV) contrast-enhanced computed tomography (CT) examination. MATERIALS AND METHODS: Institutional review board approval was obtained for this retrospective, Health Insurance Portability and Accountability Act-compliant investigation. Overall, 100 adult inpatients (50 males [mean age = 61 years, range: 24-94 years] and 50 females [mean age = 60 years, range: 20-95 years]) with stable pre-CT renal function who developed post-CT AKI using the Acute Kidney Injury Network (AKIN) laboratory criteria following an IV contrast-enhanced CT examination comprised the study population. Electronic International Classification of Disease-9 analysis followed by a comprehensive manual electronic medical record review was systematically performed by 5 radiologists to identify known acute (n = 24, within 5 days before or 3 days after CT) and chronic (n = 21) risk factors for AKI other than contrast material administration that might confound a diagnosis of contrast-induced nephrotoxicity. Descriptive statistics were performed. RESULTS: Of 100 inpatients with post-CT AKI, 99 (99%) had 1 or more acute risk factor(s) for AKI other than contrast material administration (median = 3 risk factors, range: 0-8) and 86 (86%) had one or more chronic risk factor(s) for AKI (median = 2 risk factors, range: 0-7). The median number of risk factors (acute or chronic) per patient was 5 (range: 1-13). Only 1 inpatient (1%) developed post-CT AKI without a confounding acute risk factor (estimated glomerular filtration rate = 62-71 mL/min/1.73 m(2), 4 chronic risk factors, and CT 7 days after pancreaticoduodenectomy). The most common acute risk factors were nephrotoxic medications (83%) and parenteral blood product administration (30%). The most common chronic risk factors were hypertension (59%) and chronic kidney disease (56%). CONCLUSION: Nonconfounded post-CT AKI is rare in hospitalized adults with stable renal function who have been exposed to IV low- or iso-osmolality iodinated contrast material.

Use of antihypertensive medications and diagnostic tests among privately insured adolescents and young adults with primary versus secondary hypertension.

PURPOSE: To compare the use of antihypertensive medications and diagnostic tests among adolescents and young adults with primary versus secondary hypertension. METHODS: We conducted retrospective cohort analysis of claims data for adolescents and young adults (12-21 years of age) with ≥3 years of insurance coverage (≥11 months/year) in a large private managed care plan during 2003-2009 with diagnosis of primary hypertension or secondary hypertension. We examined their use of antihypertensive medications and identified demographic characteristics and the presence of obesity-related comorbidities. For the subset receiving antihypertensive medications, we examined their diagnostic test use (echocardiograms, renal ultrasounds, and electrocardiograms). RESULTS: The study sample included 1,232 adolescents and young adults; 84% had primary hypertension and 16% had secondary hypertension. The overall prevalence rate of hypertension was 2.6%. One quarter (28%) with primary hypertension had one or more antihypertensive medications, whereas 65% with secondary hypertension had one or more antihypertensive medications. Leading prescribers of antihypertensives for subjects with primary hypertension were primary care physicians (80%), whereas antihypertensive medications were equally prescribed by primary care physicians (43%) and sub-specialists (37%) for subjects with secondary hypertension. CONCLUSIONS: The predominant hypertension diagnosis among adolescents and young adults is primary hypertension. Antihypertensive medication use was higher among those with secondary hypertension compared with those with primary hypertension. Further study is needed to determine treatment effectiveness and patient outcomes associated with differential treatment patterns used for adolescents and young adults with primary versus secondary hypertension.

Renal sonography with Doppler for detecting suspected pediatric renin-mediated hypertension - is it adequate?

BACKGROUND: Renal Doppler US is used to evaluate suspected vascular causes of hypertension in children, despite mostly unknown diagnostic performance characteristics. OBJECTIVE: To evaluate renal Doppler US for detecting vascular causes of hypertension in children with high clinical suspicion of aortic or renal artery narrowing. MATERIALS AND METHODS: We identified pediatric renal Doppler US examinations performed for hypertension between January 1995 and June 2010 at our institution. We excluded children without follow-up angiography (CT-, MR-, or catheter-based). Two pediatric radiologists reviewed imaging studies and documented relevant findings. Intrarenal spectral Doppler resistive index measurement <0.5 or tardus parvus waveform constituted a positive examination. RESULTS: Thirty-five boys and 13 girls underwent renal Doppler US and confirmatory imaging (mean age = 9.0 years). Nineteen US examinations were truly negative, two were falsely negative, 18 were truly positive (16 involved narrowing of the aorta or main renal artery) and nine were falsely positive. Sonography had a sensitivity and specificity of 90% and 68%, respectively, for detecting a vascular cause of hypertension. CONCLUSION: Renal Doppler sonography reliably detects renin-mediated hypertension caused by aortic or main renal artery narrowing in children. More studies are needed to determine its ability to detect intrarenal and accessory renal artery stenoses.

Urine podocyte mRNAs, proteinuria, and progression in human glomerular diseases.

Model systems demonstrate that progression to ESRD is driven by progressive podocyte depletion (the podocyte depletion hypothesis) and can be noninvasively monitored through measurement of urine pellet podocyte mRNAs. To test these concepts in humans, we analyzed urine pellet mRNAs from 358 adult and pediatric kidney clinic patients and 291 controls (n=1143 samples). Compared with controls, urine podocyte mRNAs increased 79-fold (P<0.001) in patients with biopsy-proven glomerular disease and a 50% decrease in kidney function or progression to ESRD. An independent cohort of patients with Alport syndrome had a 23-fold increase in urinary podocyte mRNAs (P<0.001 compared with controls). Urinary podocyte mRNAs increased during active disease but returned to baseline on disease remission. Furthermore, urine podocyte mRNAs increased in all categories of glomerular disease evaluated, but levels ranged from high to normal, consistent with individual patient variability in the risk for progression. In contrast, urine podocyte mRNAs did not increase in polycystic kidney disease. The association between proteinuria and podocyturia varied markedly by glomerular disease type: a high correlation in minimal-change disease and a low correlation in membranous nephropathy. These data support the podocyte depletion hypothesis as the mechanism driving progression in all human glomerular diseases, suggest that urine pellet podocyte mRNAs could be useful for monitoring risk for progression and response to treatment, and provide novel insights into glomerular disease pathophysiology.

The clinical impact of humoral immunity in pediatric renal transplantation.

The development of anti-donor humoral responses after transplantation associates with higher risks for acute rejection and 1-year graft survival in adults, but the influence of humoral immunity on transplant outcomes in children is not well understood. Here, we studied the evolution of humoral immunity in low-risk pediatric patients during the first 2 years after renal transplantation. Using data from 130 pediatric renal transplant patients randomized to steroid-free (SF) or steroid-based (SB) immunosuppression in the NIH-SNSO1 trial, we correlated the presence of serum anti-HLA antibodies to donor HLA antigens (donor-specific antibodies) and serum MHC class 1-related chain A (MICA) antibody with both clinical outcomes and histology identified on protocol biopsies at 0, 6, 12, and 24 months. We detected de novo antibodies after transplant in 24% (23% of SF group and 25% of SB group), most often after the first year. Overall, 22% developed anti-HLA antibodies, of which 6% were donor-specific antibodies, and 6% developed anti-MICA antibody. Presence of these antibodies de novo associated with significantly higher risks for acute rejection (P=0.02), chronic graft injury (P=0.02), and decline in graft function (P=0.02). In summary, antibodies to HLA and MICA antigens appear in approximately 25% of unsensitized pediatric patients, placing them at greater risk for acute and chronic rejection with accelerated loss of graft function. Avoiding steroids does not seem to modify this incidence. Whether serial assessments of these antibodies after transplant could guide individual tailoring of immunosuppression requires additional study.

Gaining the PROMIS perspective from children with nephrotic syndrome: a Midwest pediatric nephrology consortium study.

BACKGROUND AND OBJECTIVES: Nephrotic syndrome (NS) represents a common disease in pediatric nephrology typified by a relapsing and remitting course and characterized by the presence of edema that can significantly affect the health-related quality of life in children and adolescents. The PROMIS pediatric measures were constructed to be publically available, efficient, precise, and valid across a variety of diseases to assess patient reports of symptoms and quality of life. This study was designed to evaluate the ability of children and adolescents with NS to complete the PROMIS assessment via computer and to initiate validity assessments of the short forms and full item banks in pediatric NS. Successful measurement of patient reported outcomes will contribute to our understanding of the impact of NS on children and adolescents. DESIGN: This cross-sectional study included 151 children and adolescents 8-17 years old with NS from 16 participating institutions in North America. The children completed the PROMIS pediatric depression, anxiety, social-peer relationships, pain interference, fatigue, mobility and upper extremity functioning measures using a web-based interface. Responses were compared between patients experiencing active NS (n = 53) defined by the presence of edema and patients with inactive NS (n = 96) defined by the absence of edema. RESULTS: All 151 children and adolescents were successfully able to complete the PROMIS assessment via computer. As hypothesized, the children and adolescents with active NS were significantly different on 4 self-reported measures (anxiety, pain interference, fatigue, and mobility). Depression, peer relationships, and upper extremity functioning were not different between children with active vs. inactive NS. Multivariate analysis showed that the PROMIS instruments remained sensitive to NS disease activity after adjusting for demographic characteristics. CONCLUSIONS: Children and adolescents with NS were able to successfully complete the PROMIS instrument using a web-based interface. The computer based pediatric PROMIS measurement effectively discriminated between children and adolescents with active and inactive NS. The domain scores found in this study are consistent with previous reports investigating the health-related quality of life in children and adolescents with NS. This study establishes known-group validity and feasibility for PROMIS pediatric measures in children and adolescents with NS.

Underlying Rationale and Approach to Treat Hypertension in Adolescents by Physicians of Different Specialty.

OBJECTIVE: To describe the underlying clinical decision-making rationale among general pediatricians, family physicians, pediatric cardiologists and pediatric nephrologists in their approach to an adolescent with hypertension. METHODS: We conducted semi-structured phone interviews with a convenience sample of physicians from the above-mentioned 4 specialties. Each participant was asked to "think aloud" regarding their approach to a hypothetical patient - 12 year old boy with persistent hypertension for 6 months. Standardized open-ended questions about potential factors that could affect physicians' diagnosis and treatment strategies (e.g., patient age) were used. Interviews were audio-recorded; transcribed verbatim; transcripts were independently coded by 2 investigators; emergent themes identified and inter-coder agreement achieved. Thematic analysis was performed based on grounded theory. RESULTS: Nineteen participants included 5 general pediatricians, 5 pediatric cardiologists, 5 pediatric nephrologists and 4 family physicians. Five themes emerged: 1) Accuracy of blood pressure measurement and hypertension diagnosis, 2) Shift in the epidemiology of pediatric hypertension from secondary to primary hypertension, 3) Patient characteristics considered in the decision to initiate workup, 4) Obesity-centered choice of diagnostic tests and lifestyle modifications, and 5) Variable threshold for initiating antihypertensive pharmacotherapy vs. referral to hypertension specialists. CONCLUSIONS: There is variation across primary care and specialty physicians who provide care for children and adolescents with hypertension. Key areas of variability include the willingness to initiate antihypertensive medications, the use of diagnostic tests (e.g., ambulatory blood pressure monitoring), and the perceived need for specialty referral. Further study is needed to assess whether different treatment paradigms result in differential patient outcomes.

Use of diagnostic tests in adolescents with essential hypertension.

OBJECTIVE: To describe the use of diagnostic tests in adolescents with essential hypertension. DESIGN: Longitudinal analysis of administrative claims data. SETTING: Michigan Medicaid program during 2003 to 2008. PARTICIPANTS: Adolescents with 3 or more years of Medicaid eligibility (≥ 11 months/y) who had a diagnosis of essential hypertension and 1 or more antihypertensive medication pharmacy claims. MAIN OUTCOME MEASURES: We examined adolescents' echocardiogram use and compared it with electrocardiogram (EKG) and renal ultrasonography use. We examined timing of the 3 diagnostic tests in relation to the first pharmacy claim. We examined patient demographics and presence of obesity-related comorbidities. RESULTS: During 2003 to 2008, there were 951 adolescents with essential hypertension who had antihypertensive pharmacy claims; 24% (226) had echocardiograms; 22% (207) had renal ultrasonography; and 50% (478) had EKGs. Males (odds ratio [OR], 1.53; 95% CI, 1.06-2.21), younger adolescents (OR, 1.69; 95% CI, 1.17-2.44), those who had EKGs (OR, 5.79; 95% CI, 4.02-8.36), and those who had renal ultrasonography (OR, 2.22; 95% CI, 1.54-3.20) were more likely to obtain echocardiograms compared with females, older adolescents, and adolescents who did not have EKGs or renal ultrasonography. CONCLUSIONS: Guideline-recommended diagnostic tests-echocardiograms and renal ultrasonography-were equally poorly used by adolescents with essential hypertension. Sex and age differences exist in the use of echocardiograms by adolescents with essential hypertension. The decision and choice of diagnostic tests to evaluate adolescents with essential hypertension warrant further study to understand the underlying rationale for those decisions and to determine treatment effectiveness.