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Currently, there is no consensus among pediatric kidney transplant centers regarding the use and regimen for immunosuppressive induction therapy.In this single center, retrospective cohort study, pediatric kidney transplant recipients transplanted between 1 May 2013 and 1 May 2018 with rabbit antithymocyte globulin (rATG) induction were included. We stratified patients based on immunological risk, with high risk defined as those with repeat transplant, preformed donor specific antibody, current panel-reactive antibodies 20%, 0 antigen match and/or African-American heritage. Outcome of interest was the incidence of biopsy proven acute rejection by 1 year.A total of 166 patients met inclusion criteria. Age of patients was 12 years (11 mo-21 y), (median, range), 21.5% received a living donor transplant and 50.6% were female. Low-immunologic-risk patients were divided into 2 groups, those who received the lower cumulative rATG dose of ≤ 3.5 mg/kg (n = 52) versus the higher cumulative dose of 3.5 mg/kg (n = 47). The median total dose in the lower dose group was 3.1 (IQR 0.3) and 4.4 (IQR 0.8) in the higher dose group, P 0.001. Rejection rate did not differ significantly between the 2 treatment groups (7/52 vs. 6/47). None in the lower dose group developed BK nephropathy versus 3 in the higher dose group. Graft loss due to BK nephropathy occurred in 1 patient in the higher dose group. Graft loss in the whole cohort at 12 months was a rare event (n = 1) with 99.5% graft survival and 100% patient survival.Reduced rATG dosing (≤ 3.5 mg/kg) when compared to higher dosing ( 3.5 mg/kg) is safe and effective in low-risk pediatric kidney transplant recipients without increasing risk of rejection. A higher resolution version of the Graphical abstract is available as Supplementary information.

Background: Hypertension (HTN) has been recognized as an evolving problem in the pediatric population with concern for increasing incidence. Normative values of blood pressure (BP) in children and definition of HTN in the outpatient setting exist, which cannot be reliably used for inpatient treatment and therapy initiation, because of several factors unique to the inpatient setting. No normative exists to describe HTN in hospitalized pediatric populations. We aimed to produce normative BP values for hospitalized pediatric patients in the acute care setting. Methods: We conducted a cross sectional observational study among all children hospitalized on the acute care floors, ≥ 2 and < 18 years of age, at Stanford Children’s Hospital, from Jan-01-2014 to Dec-31-2018. Our cohort included 4112 patients with a total of 118,423 automated, oscillometric, BPs measured in the upper extremity during a hospitalization of >24 hours. Results: In our cohort the overall prevalence of HTN, defined by outpatient guidelines, was 14-41% in boys and 7-34% in girls. Centile curves (Figure 1) were derived from the data set and demonstrated an overall higher BP reading for hospitalized patients when compared to the outpatient setting. Conclusion: Higher blood pressures are anticipated during hospitalization compared to patients in the ambulatory setting, hence outpatient 2017 clinical practice guidelines cannot be reliably used for inpatient treatment and therapy initiation. The thresholds provided by the centile curves may provide the clinician with some guidance how to manage hospitalized pediatric patients based on clinical circumstances.

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.

BACKGROUND: Hypertension is a risk factor for posterior reversible encephalopathy syndrome (PRES), but the timing and severity of hypertension relative to PRES are unknown. The objective was to identify a clinically meaningful blood pressure (BP) threshold that predicts PRES development in high-risk children. METHODS: We recorded peak systolic BP, diastolic BP, BP z-scores, and mean arterial pressure over the 14 days preceding clinical concern for PRES in 35 subjects who developed PRES, compared to 14 controls who had normal brain magnetic resonance imaging and similar underlying disease, renal function, and medications. We used multivariable logistic regression models adjusted for fluid overload and obesity to estimate the association of peak BP with PRES. We used receiver operating characteristic curves to determine which peak BP thresholds best predicted PRES and calculated the corresponding sensitivity, specificity, and positive and negative predictive values. RESULTS: Peak systolic BP z-score was most strongly associated with PRES (OR 3.97, 95% CI 1.62–9.74), and peak systolic BP z-score ≥ 3.0 predicted PRES (area under the curve 0.95, 95% CI 0.88–1.0) with 91% sensitivity and 85% specificity, indicating 94% positive predictive value and 79% negative predictive value. CONCLUSIONS: We demonstrated that peak systolic BP z-score ≥ 3.0 in the preceding 14 days predicted PRES development in cases compared with controls in children at high risk. Our study suggests that stage 2 hypertension, corresponding to a z-score ≥ 3.0, could help define hypertensive emergency in high-risk children and indicate when more aggressive treatment is warranted to prevent neurologic injury.

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).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.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.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.

COVID-19 vaccination has been successful in decreasing rates of SARS-CoV-2 infection in areas with high vaccine uptake. Cases of breakthrough SARS-CoV-2 infection remain infrequent among immunocompetent vaccine recipients who are protected from severe COVID-19. Robust data demonstrate the safety, immunogenicity, and effectiveness of several COVID-19 vaccine formulations. Importantly, Pfizer-BioNTech BNT162b2 mRNA COVID-19 vaccine studies have now included children as young as 5 years of age with safety, immunogenicity, and effectiveness data publicly available. In the United States, emergency use authorization by the Federal Drug Administration and approval from the Centers for Disease Control/Advisory Committee on Immunization Practices have been provided for the 5- to 11-year-old age group.Members of the International Pediatric Transplant Association (IPTA) provide an updated review of current COVID-19 vaccine data with focus on pediatric solid organ transplant (SOT)-specific issues.This review provides an overview of current COVID-19 immunogenicity, safety, and efficacy data from key studies, with focus on data of importance to pediatric SOT recipients. Continued paucity of data in the setting of pediatric transplantation remains a challenge.Further studies of COVID-19 vaccination in pediatric SOT recipients are needed to better understand post-vaccine COVID-19 T-cell and antibody kinetics and determine the optimal vaccine schedule. Increased COVID-19 vaccine acceptability, uptake, and worldwide availability are needed to limit the risk that COVID-19 poses to pediatric solid organ transplant recipients.

Cardiovascular manifestations occur in over 80% of Williams syndrome (WS) patients and are the leading cause of morbidity and mortality. One-third of patients require cardiovascular surgery. Renal artery stenosis (RAS) is common in WS. No studies have assessed postoperative cardiac surgery-related acute kidney injury (CS-AKI) in WS. Our objectives were to assess if WS patients have higher risk of CS-AKI postoperatively than matched controls and if RAS could contribute to CS-AKI.This was a retrospective study of all patients with WS who underwent cardiac surgery at our center from 2010 to 2020. The WS study cohort was compared with a group of controls matched for age, sex, weight, and surgical procedure.Patients underwent cardiac surgery and postoperative care at Lucile Packard Children's Hospital Stanford.There were 27 WS patients and 43 controls (31% vs 42% female; p = 0.36). Median age was 1.8 years (interquartile range [IQR], 0.7-3.8 yr) for WS and 1.7 years (IQR, 0.8-3.1 yr) for controls.None.Postoperative hemodynamics, vasopressor, total volume input, diuretic administration, and urine output were collected in the first 72 hours. Laboratory studies were collected at 8-hour intervals. Multivariable analysis identified predictors of CS-AKI.Controlled for renal perfusion pressure (RPP) and vasoactive inotrope score (VIS), compared with controls, the odds ratio (OR) of CS-AKI in WS was 4.2 (95% CI, 1.1-16; p = 0.034). Higher RPP at postoperative hours 9-16 was associated with decreased OR of CS-AKI (0.88 [0.8-0.96]; p = 0.004). Increased VIS at hour 6 was associated with an increased OR of CS-AKI (1.47 [1.14-1.9]; p = 0.003). Younger age was associated with an increased OR of CS-AKI (1.9 [1.13-3.17]; p = 0.015).The OR of CS-AKI is increased in pediatric patients with WS compared with controls. CS-AKI was associated with VIS at the sixth postoperative hour. Increases in RPP and mean arterial pressure were associated with decreased odds of CS-AKI.

High tacrolimus intrapatient variability has been associated with inferior graft outcomes in patients with kidney transplants. We studied baseline patterns of tacrolimus intrapatient variability in pediatric patients with kidney transplants and examined these patterns in relation to C1q-bindingAll tacrolimus levels in participants who underwent kidney-only transplantation at a single pediatric center from 2004 to 2018 (with at least 12-month follow-up, followed until 2019) were analyzed to determine baseline variability. Intrapatient variability was defined using the coefficient of variation (SD/mean ×100%) of all samples in a 6-month moving window. RoutineTacrolimus intrapatient variability developed a steady-state baseline of 30% at 10 months post-transplant in 426 patients with a combined 31,125 tacrolimus levels. Included in the outcomes study were 220 patients, of whom 51 developed C1q-bindingHigh tacrolimus intrapatient variability was strongly associated with

BACKGROUND AND OBJECTIVES: In December 2014, the Kidney Allocation System (KAS) was implemented to improve equity in access to transplantation, but preliminary studies in children show mixed results. Thus, we aimed to assess how the 2014 KAS policy change affected racial and ethnic disparities in pediatric kidney transplantation access and related outcomes. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We performed a retrospective cohort study of children

Antibody-mediated rejection is a common cause of early kidney allograft loss but the specifics of antibody measurement, therapies and endpoints have not been universally defined. In this retrospective study, we assessed the performance of risk stratification using systematic donor-specific antibody (DSA) monitoring. Included in the study were children who underwent kidney transplantation between January 1, 2010 and March 1, 2018 at Stanford, with at least 12-months follow-up. A total of 233 patients were included with a mean follow-up time of 45 (range, 9–108) months. Median age at transplant was 12.3 years, 46.8% were female, and 76% had a deceased donor transplant. Fifty-two (22%) formed C1q-binding de novo donor-specific antibodies (C1q-dnDSA). After a standardized augmented immunosuppressive protocol was implemented, C1q-dnDSA disappeared in 31 (58.5%). Graft failure occurred in 16 patients at a median of 54 (range, 5–83) months, of whom 14 formed dnDSA. The 14 patients who lost their graft due to rejection, all had persistent C1q-dnDSA. C1q-binding status improved the individual risk assessment, with persistent; C1q binding yielding the strongest independent association of graft failure (hazard ratio, 45.5; 95% confidence interval, 11.7–177.4). C1q-dnDSA is more useful than standard dnDSA as a noninvasive biomarker for identifying patients at the highest risk of graft failure.

Background Population‐level COVID‐19 immunization will play a key role in slowing down the SARS‐CoV‐2 pandemic on a global scale and protect the most at‐risk individuals. Thanks to a formidable universal effort, several SARS‐CoV‐2 vaccines have been marketed less than a year since the first documented COVID‐19 case, with promising safety, efficacy, and immunogenicity results in adults. As children were not included in the initial trials, no vaccine is currently approved for individuals

The COVID‐19 pandemic has proven to be a challenge in regard to the clinical presentation, prevention, diagnosis, and management of SARS‐CoV‐2 infection among children who are candidates for and recipients of SOT. By providing scenarios and frequently asked questions encountered in routine clinical practice, this document provides expert opinion and summarizes the available data regarding the prevention, diagnosis, and management of SARS‐CoV‐2 infection among pediatric SOT candidates and recipients and highlights ongoing knowledge gaps requiring further study. Currently available data are still lacking in the pediatric SOT population, but data have emerged in both the adult SOT and general pediatric population regarding the approach to COVID‐19. The document provides expert opinion regarding prevention, diagnosis, and management of SARS‐CoV‐2 infection among pediatric SOT candidates and 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.

Diarrhea in the pediatric solid organ transplantation (SOT) recipient is a frequent complaint that is associated with significant morbidity and impaired quality of life. There are limited published data regarding the specific epidemiology, diagnostic evaluation, and treatment of diarrhea after SOT in children. Pediatric SOT recipients have an increased risk of developing diarrhea because of a generalized immunosuppressed state, epidemiologic exposures, and polypharmacy. There is a need to standardize the diagnostic evaluation of diarrhea in children after SOT to facilitate an accurate diagnosis and timely treatment. Herein, we review the available published data and propose a systematic, stepwise approach to the evaluation of diarrhea in this high-risk population, focusing on timely diagnosis of both infectious and non-infectious causes, in order to provide focused management. Prospective studies are needed to better assess the true prevalence, risk factors for, etiologies, and complications of diarrhea in pediatric SOT patients that will guide optimal management. Development of effective vaccines and antiviral therapies for enteric viruses may also contribute to improved outcomes.

BACKGROUND: Varicella and measles infections can be life-threatening after solid organ transplantation (SOT) but may be preventable with live-attenuated vaccines (LAV). METHODS: This survey conducted in January 2019 among subscribers of the International Pediatric Transplantation Association listserv aimed to explore the current strategies to prevent and manage both infections in the pediatric SOT population, including recommending LAV after SOT. RESULTS: The answers given by 95 pediatric SOT healthcare workers show that these strategies are not yet optimal and call for further education. In particular, 59% of respondents are unnecessarily waiting for a SOT candidate to be >1 year of age to start administrating LAV before SOT. Interestingly, most respondents are willing to administer LAV after SOT (57%), and a fifth (21%) are already doing so, off-label. The survey queried the precautions taken to improve safety evaluations after LAV, and identified knowledge gaps and practitioners' concerns. CONCLUSION: The results of this survey could be used as a starting point for education and promotion of the safe administration of LAV in carefully selected SOT recipients; in turn, this would increase available data that would contribute to the development of evidence-based guidelines by the transplant societies and ultimately prevent these infections after SOT.

INTRODUCTION Urinary diversion in pediatric renal transplant candidates with bladders not amenable to primary reconstruction can be achieved by pre-transplant ileal conduit creation. We performed cutaneous ureterostomies to limit pre-transplant surgery, protect the peritoneum for dialysis, transplant patients sooner, and preserve ureter length for future surgical reconstruction. METHODS We compared four pediatric transplant recipients with ureterostomies to four recipients with ileal conduits from 2009 to 2017. RESULTS All patients with ileal conduits developed at least one urinary tract infection (UTI) within 1 year of transplant and three of four patients had recurrent UTIs within the first year. Two patients required ileal conduit revisions for redundant conduits and recurrent UTIs. Of the four ureterostomy patients, two patients had UTIs within one year of transplant. Two patients developed ureterostomy strictures requiring revision at the fascial level; one was associated with a UTI. CONCLUSION In our small case series, ureterostomy allowed for a single operative intervention with preservation of ureter length for later reconstruction. Ureterostomy is safe and recurrent UTI may be lower in the ureterostomy group. Long-term evaluation of ureterostomy for urinary diversion in pediatric kidney transplant is warranted.

Introduction The presence of infections in the immediate pretransplant period poses challenges in decision-making. Delaying transplantation because of these infections may be required, but is associated with a risk to the potential recipient. The aim of this project was to develop a structured framework based on expert opinion to guide decision-making regarding the safety of transplantation for candidates with infection immediately before transplant, and to show how this framework can be applied to clinical scenarios. Methods Categories were created as follows: Category A: no delay; Category B: brief delay (≤1 week); Category C: intermediate delay (>1 week); and Category D: more prolonged or indefinite delay. A survey containing 59 clinical scenarios was sent to members of the IPTA ID CARE committee. Answers were reviewed, and the level of agreement was characterized as follows: Level 1: ≥75% agreement; Level 2:51%-74% agreement; and Level 3: ≤50% agreement. 95% CIs were calculated for the mean overall agreement across 59 scenarios. Results Among the panel, the agreement level ranged from 33% to 92% with the mean overall agreement across the 59 scenarios being 61%. For 7/59 scenarios, the lower bound of 95% CI was greater than 50%, indicating a difference at the 5% level of significance between the observed proportion and the chance level of 0.5. Summary The document provides expert opinion regarding the need to delay transplantation in the setting of different infections. The most important points in the decision to proceed to SOT included the urgency of transplantation and the severity of infection.

Allocation of deceased donor kidneys is based on several criteria; however, the final decision to accept or reject the offered kidney is made by the potential recipient's transplant team (surgeon/nephrologist). Several considerations including assessment of the donor quality, the HLA match between the donor and the recipient, several recipient factors, the geographical location of the recipient, and the organ all affect the decision of whether or not to finally accept the organ for a particular recipient. This decision needs to be made quickly, often on the spot. Maximizing the benefit from this scarce resource raises difficult ethical issues. The philosophies of equity and utility are often competing. This article will discuss the several considerations for the pediatric nephrologist while accepting a deceased donor kidney for a particular pediatric patient.

Background We evaluated and compared the effects of sparsentan, a dual endothelin type A (ET A ) and angiotensin II type 1 receptor antagonist, with those of the angiotensin II type 1 receptor antagonist irbesartan in patients with primary FSGS. Methods In this phase 2, randomized, double-blind, active-control Efficacy and Safety of Sparsentan (RE-021), a Dual Endothelin Receptor and Angiotensin Receptor Blocker, in Patients with Focal Segmental Glomerulosclerosis (FSGS): A Randomized, Double-blind, Active-Control, Dose-Escalation Study (DUET), patients aged 8–75 years with biopsy-proven FSGS, eGFR>30 ml/min per 1.73 m 2 , and urinary protein-to-creatinine ratio (UP/C) ≥1.0 g/g received sparsentan (200, 400, or 800 mg/d) or irbesartan (300 mg/d) for 8 weeks, followed by open-label sparsentan only. End points at week 8 were reduction from baseline in UP/C (primary) and proportion of patients achieving FSGS partial remission end point (FPRE) (UP/C: ≤1.5 g/g and >40% reduction [secondary]). Results Of 109 patients randomized, 96 received study drugs and had baseline and week 8 UP/C measurements. Sparsentan-treated patients had greater reductions in UP/C than irbesartan-treated patients did when all doses (45% versus 19%; P =0.006) or the 400 and 800 mg doses (47% versus 19%; P =0.01) were pooled for analysis. The FSGS partial remission end point was achieved in 28% of sparsentan-treated and 9% of irbesartan-treated patients ( P =0.04). After 8 weeks of treatment, BP was reduced with sparsentan but not irbesartan, and eGFR was stable with both treatments. Overall, the incidence of adverse events was similar between groups. Hypotension and edema were more common among sparsentan-treated patients but did not result in study withdrawals. Conclusions Patients with FSGS achieved significantly greater reductions in proteinuria after 8 weeks of sparsentan versus irbesartan. Sparsentan was safe and well tolerated.

The blood pressure (BP) burden is high in pediatric hemodialysis (HD) patients and adversely affects prognosis. The aim of this study was to examine whether 44-h ambulatory BP monitoring (ABPM) provides additional relevant BP data compared with 24-h ABPM.ABPM was initiated at the end of the mid-week dialysis run in 13 stable pediatric HD patients and continued until the next run for 44 h. Day 1 was defined as the initial 24-h ABPM and Day 2 as the time period after that until the next dialysis run. All patients had an echocardiogram to calculate the left ventricular mass index (LVMI).A higher percentage of patients were diagnosed with hypertension from the 44-h ABPM than from the 24-h ABPM. All BP indexes and loads (except nighttime diastolic load) were significantly higher on Day 2 than on Day 1. Patients with BP loads of ≥ 25 % on 44-h ABPM had significantly higher LVMI than those patients with normal BP loads. No such association was found with 24-h ABPM and LVMI. Higher interdialytic weight gain was associated with higher Day-2 nighttime systolic BP load.The 44-h ABPM provides more information than the 24-h ABPM in terms of diagnosing and assessing the true burden of hypertension in pediatric HD patients. Elevated BP loads from 44-h ABPM correlate with a higher LVMI on the echocardiogram.

Atypical hemolytic uremic syndrome (aHUS) evolves into end-stage renal failure in nearly half of affected patients and is associated with defective regulation of the alternative complement pathway. Patients with a complement factor H (CFH) mutation have a 30-100% risk of graft loss due to aHUS recurrence or graft thrombosis. Since CFH is produced predominantly by the liver, combined liver-kidney transplant is a curative treatment option. One major unexpected risk includes liver failure secondary to uncontrolled complement activation. We report a successful combined liver-kidney transplantation with perioperative plasma exchange and use of the humanized anti-C5 monoclonal antibody eculizumab.An 11-month-old female presented with oliguric renal failure after 3 weeks of flu-like symptoms in the absence of diarrhea. Following the identification of Escherichia coli 0157:H7 in her stool, she was discharged home on peritoneal dialysis with a diagnosis of Shiga toxin-associated HUS. Three months later, she developed severe anemia, thrombocytopenia, and neurological involvement. aHUS was diagnosed and confirmed, and genetic testing revealed a mutation in CFH SCR20. Once donor organs became available, she received preoperative plasma exchange followed by eculizumab infusion with intra-operative fresh frozen plasma prior to combined liver-kidney transplant. At 19 months post-transplant, she continues to have excellent allograft and liver function without signs of disease recurrence.Perioperative use of eculizumab in conjunction with plasma exchange during simultaneous liver-kidney transplant can be used to inhibit terminal complement activity, thereby optimizing successful transplantation by reducing the risk of graft thrombosis.

Congenital nephrotic syndrome (CNS) of the Finnish type due to mutation in the NPHS-1 gene results in massive proteinuria due to structural abnormality in the glomerular slit diaphragm, and is usually refractory to immunosuppressive therapy. Patients eventually require bilateral nephrectomy and renal replacement therapy, with transplantation being the ultimate goal. Post-transplant recurrence of nephrotic syndrome occurs in about 25% of children and is thought to be immune-mediated secondary to antibodies formed against the nephrin protein in renal allograft. Conventional therapy with calcineurin inhibitors (CNI), cyclophosphamide and corticosteroids with or without plasmapheresis often fails to achieve remission resulting in graft loss in 12-16%. There is limited experience with use of rituximab (RTX) in pediatric organ transplant recipients. We report the first case of post-transplant recurrence of nephrotic syndrome in a 4-yr-old child with CNS due to NPHS-1 mutation in whom CNI, corticosteroid and cyclophosphamide therapy was unsuccessful, but who achieved remission after depletion of B cells with RTX, associated with a decrease in the level of anti-nephrin antibodies. The child remains in remission 5 yr following treatment. Our experience suggests that activated B cells may play a pivotal role in the recurrence of nephrosis after renal transplantation in children with CNS.

Summary Background and objectives Pre- or postdialysis BP recordings are imprecise, can be biased, and have poor test– retest reliability in children on dialysis. We aimed to examine the possible differences between pre- and postdialysis BP levels and 24-hour ambulatory BP monitoring (ABPM) in diagnosis of hypertension (HTN). Design, setting, participants, & measurements Twenty-four children on dialysis had 24-hour ABPM in the interdialytic period, and values were compared with average pre- and postdialysis systolic BP (SBP) and diastolic BP (DBP) recordings that week. Each patient had an echocardiogram to determine presence of left ventricular hypertrophy (LVH). Results By ABPM, 8% of patients had white coat HTN and 12% had masked HTN. There was no significant difference in diagnosis of systolic HTN based on ABPM daytime SBP mean or load and postdialysis SBP. However, only 15% of patients had diastolic HTN based on postdialysis measures, whereas 46% of patients had significantly elevated daytime DBP loads and 71% had high nighttime DBP loads on ABPM. Fortyeight percent of patients were SBP nondippers. Children with LVH had higher daytime and nighttime SBP loads, significantly higher daytime and nighttime DBP loads, and lesser degree of nocturnal dipping of SBP compared with those who did not. Conclusion ABPM is more informative than pre- and postdialysis BPs and improves the predictability of BP as a risk factor for target organ damage. Diagnosis and treatment monitoring of HTN among pediatric dialysis patients is enhanced with addition of ABPM. Clin J Am Soc Nephrol 6: 870–876, 2011. doi: 10.2215/CJN.07960910

Antibodies (Ab) responses to major and minor human leukocyte antigen loci may impact graft survival after organ transplantation.A ProtoArray platform was used to study 37 serum samples from 15 renal transplant patients with (n=10) and without (n=5) acute rejection (AR) and seven normal controls, and the clinical relevance of major histocompatibility complex class I chain-related gene-A (MICA)-Ab measurements were investigated. Biopsy immunohistochemistry was conducted for localization of the MICA antigen.De novo MICA-Ab were detected in 11 of the 15 transplant patients in this study, irrespective of interval acute graft rejection. Mean MICA-Ab signal intensity was higher in transplant patients with C4d+AR (121.4) versus C4d-AR (4.3), correlated with donor-specific Ab to human leukocyte antigens (r=0.66, P=0.0078), was not elevated in cellular rejections, and correlated with decline in graft function over the subsequent year (r=0.73, P=0.0022). Integrative genomics accurately predicted localization of the MICA antigen to the glomerulus in the normal kidney (Li et al. Proc Natl Acad Sci USA 2009; 106: 4148), because this was confirmed subsequently by immunohistochemistry.Integrative genomics analysis of ProtoArray data is a powerful tool to ascertain de novo antibody responses after renal transplantation and to accurately predict the anatomical location of the target renal antigens. This proof-of-concept study on MICA measurements by ProtoArray demonstrates that antibody responses modulated to MICA after transplantation in patients, irrespective of graft rejection, may be high at the time of humoral rejection and may not be elevated in cellular rejection. Understanding that MICA is preferentially localized to the glomerulus may explain both immunoregulatory and pathogenic roles for MICA after transplantation.

Post-transplant clinical disease with cytomegalovirus (CMV) and Epstein-Barr virus (EBV) is a known risk factor for graft dysfunction and lymphoproliferation. We postulate that subclinical, asymptomatic viremia also adversely impacts outcomes, and may warrant re-assessment of current monitoring and antiviral prophylaxis protocols. A single-center study was conducted on 102 pediatric (51 steroid-free and 51 matched steroid-based historical controls). Quantitative viral loads were serially monitored and correlated with outcome measures. Overall, the incidence of CMV and EBV clinical disease was 5% (1% CMV and 4% EBV); however, the incidence of subclinical viremia was 44% (12.7% CMV, 38.2% EBV, 6.9% CMV + EBV). Risk factors for subclinical viremia were EBV naivety (p = 0.07), age less than five yr (p = 0.04), lack of prophylaxis (p = 0.01), and steroid usage (p = 0.0007). Subclinical viremia was associated with lower three-yr graft function (p = 0.03), increased risk of acute rejection (odds ratio 2.07; p = 0.025), hypertension (p = 0.04), and graft loss (p = 0.03). Subclinical asymptomatic CMV and EBV viremia is a risk factor for graft injury and loss. These findings support the need for aggressive, serial viral monitoring to better determine the appropriate length of post-transplant antiviral prophylaxis, and to determine the effect of immunosuppression protocols on the development of viremia.

Nephropathic cystinosis is a rare disorder causing the accumulation of intracellular cystine crystals in tissues. The damage to the proximal tubules of the kidneys results in Fanconi syndrome, and patients with cystinosis experience the progression of chronic kidney disease, resulting in the need for kidney transplantation. Treatment of cystinosis with cysteamine has proven to be effective; however, it has many gastrointestinal side effects that are concerning for transplant specialists during the immediate post-transplant period. Transplant specialists routinely discontinue cysteamine therapy for up to six weeks to ensure proper immunosuppressant absorption. This practice is worrisome because it communicates the acceptability of lapses of cysteamine treatment to patients. It may be better to re-initiate cysteamine therapy shortly after transplantation while the patient is followed more closely by the transplant team. This report presents two pediatric patients with nephropathic cystinosis who successfully restarted cysteamine therapy in the immediate post-transplant period without issue in regard to immunosuppression absorption or gastrointestinal side effects. These cases challenge current practice of discontinuing cysteamine therapy during kidney transplantation, and immediate re-initiation of cysteamine therapy in cystinosis patients post-transplant should be considered.

Renal transplantation is the treatment of choice for children with end-stage renal disease. More than 50% of children receive a deceased donor renal transplant. Marked disparity between the number of children on the renal transplant wait list and the supply has prompted numerous advances to increase supply as well as maximize the utility of donor organs. Allocation of deceased donor kidneys is based on several criteria. The organ allocation system policy is continually evaluated and changed incrementally to optimize allocation. We, in the United States, are in the process of transitioning into a new kidney allocation system to enhance post-transplant survival benefit, increase utilization of donated kidneys, and increase transplant access for biologically disadvantaged candidates. This review will provide a brief overview of the organ sharing system in the United States, compare the "old" and the "new" allocation system, and discuss the considerations for the pediatric nephrologist while accepting a deceased donor kidney for a particular pediatric patient.

The expansion of the number of children on the deceased donor renal transplant waitlist has far outstripped the supply of organs in most countries, leading to numerous adjustments to increase supply and to maximize the utility of donor organs. The system for organ allocation varies by country based on local laws, priorities, and resources. Adjustments are made to optimize allocation, enhance post-transplant survival benefit, decrease unequal transplant access, and optimize utilization of donated kidneys. Allocation of deceased donor kidneys is based on several criteria; however, the final decision to accept or reject the offered kidney is made by the potential recipient’s transplant team (surgeon/nephrologist). Several considerations including assessment of the donor quality, the human leukocyte antigen (HLA) match between the donor and the recipient, numerous recipient factors, the geographical location of the recipient, and the organ all affect the decision to accept the organ or not for a particular recipient. This decision must be made quickly, often on the spot. Maximizing the benefit from this scarce resource raises difficult ethical issues. The philosophies of equity and utility are often competing. In this manuscript, we highlight a representative case that helps to focus on important issues for the pediatric nephrologist to consider while making the decision to accept a deceased donor kidney offer for a particular pediatric patient.

Management of pediatric renal transplant patients involves multifactorial monitoring modalities to ensure allograft survival and prevent opportunistic infection secondary to immunosuppression. An ICFA, which utilizes CD4 T-cell production of ATP to assess immune system status, has been used to monitor transplant recipients and predict susceptibility of patients to rejection or infection. However, the validity of this assay to reflect immune status remains unanswered. In a two-yr retrospective study that included 31 pediatric renal transplant recipients, 42 patient blood samples were analyzed for immune cell function levels, creatinine, WBC (white blood cell) count, immunosuppressive drug levels, and viremia, concurrent with renal biopsy. T-cell ATP production as assessed by ICFA levels did not correlate with allograft rejection or with the presence or absence of viremia. ICFA levels did not correlate with serum creatinine or immunosuppressive drug levels, but did correlate with WBC count. The ICFA is unreliable in its ability to reflect immune system status in pediatric renal transplantation. Further investigation is necessary to develop methods that will accurately predict susceptibility of pediatric renal transplant recipients to allograft rejection and infection.

We hypothesized that the percent change in resistance (%RΔ) from bioimpedance analysis (BIA) measurements during hemodialysis (HD) can provide information on pediatric HD patients’ hydration status. Whole-body single-frequency BIA measurements were obtained before HD, each hour on HD, and after HD during two HD sessions. Pre-and post-HD weights, blood pressures, Crit-Line® measurements, and intradialytic symptoms were collected on the day of the BIA measurements. One hundred and thirty BIA measurements were obtained from 14 HD patients. The group was 43 % girls, and the mean age was 13.2 ± 4.4 years. Percent change in resistance was 13.5 ± 10.8 % at the end of HD; %RΔ correlated with percent body weight change (%BWΔ) following HD (r = −0.83, P

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.

Pediatric hypertension (HTN) is a growing concern and should be diagnosed and treated aggressively to reduce the global disease burden. Ambulatory blood pressure monitoring (ABPM) is a useful clinical tool providing a more accurate description of the patient’s blood pressure (BP) than office BP measurements, and can be considered the “gold standard” in the evaluation of the pediatric patient with a concern for HTN. The American Heart Association have suggested criteria for diagnosing ambulatory HTN, and research continues into further clarification of how to best utilize the large volume of data obtained from an ABPM report. ABPM has some limitations; however, the advantages far outweigh these. Routine use of ABPM is recommended among clinicians to better evaluate and assess the severity of a child’s HTN, and for proper management in order to prevent target organ damage and the resulting sequelae, thereby reducing the burden of cardiovascular risk in hypertensive children and adolescents.

Background The challenge of immunosuppression in pediatric renal transplantation is to balance preventing rejection while avoiding infectious complications. A dermatological complication of immunosuppression is viral warts, which cause significant disfigurement and increase the risk of skin malignancy. Methods We present three pediatric and adolescent renal allograft recipients with multiple, recalcitrant verrucae vulgares lesions and one patient with molluscum contagiosum who were switched from mycophenolate mofetil to leflunomide. Teriflunomide metabolite levels were carefully maintained between 50,000 and 100,000 ng/mL to balance its immunosuppressive and antiviral properties. No adverse events requiring discontinuation of leflunomide were encountered. Results Switching from mycophenolate mofetil to leflunomide successfully cleared verrucae vulgares and molluscum lesions in all four renal transplant patients. Conclusions The ability to minimize and even resolve warts can improve quality of life by reducing risk of skin malignancies and emotional distress in solid organ transplant patients. Leflunomide is a potential therapeutic option for posttransplantation patients with skin warts because it serves both as an adjunct to the immunosuppressive regimen and an antiviral agent.

Congenital nephrotic syndrome (CNS) of the Finnish type due to mutation in the NPHS-1 gene results in massive proteinuria due to structural abnormality in the glomerular slit diaphragm, and is usually refractory to immunosuppressive therapy. Patients eventually require bilateral nephrectomy and renal replacement therapy, with transplantation being the ultimate goal. Post-transplant recurrence of nephrotic syndrome occurs in about 25% of children and is thought to be immune-mediated secondary to antibodies formed against the nephrin protein in renal allograft. Conventional therapy with calcineurin inhibitors (CNI), cyclophosphamide and corticosteroids with or without plasmapheresis often fails to achieve remission resulting in graft loss in 12-16%. There is limited experience with use of rituximab (RTX) in pediatric organ transplant recipients. We report the first case of post-transplant recurrence of nephrotic syndrome in a 4-yr-old child with CNS due to NPHS-1 mutation in whom CNI, corticosteroid and cyclophosphamide therapy was unsuccessful, but who achieved remission after depletion of B cells with RTX, associated with a decrease in the level of anti-nephrin antibodies. The child remains in remission 5 yr following treatment. Our experience suggests that activated B cells may play a pivotal role in the recurrence of nephrosis after renal transplantation in children with CNS.

Background. Given the recent withdrawal of daclizumab (DAC), the safety and efficacy of thymoglobulin (TMG) was tested as an alternative induction agent for steroid-free (SF) immunosuppression in pediatric kidney transplant recipients. Methods. Thirteen pediatric renal transplant recipients meeting defined high-risk criteria at transplantation were offered TMG induction and SF immunosuppression with maintenance mycophenolate mofetil and tacrolimus between October 2008 and January 2010. Patients were closely monitored at baseline, 3, 6, 9, and 12 months posttransplant for protocol biopsy and clinical outcomes. Outcomes were compared with 13 consecutively transplanted low-risk patients receiving an established DAC-based SF protocol (Sarwal et al., WA, American Transplant Congress 2003). Results. There was a significant trend for overall decrease in the absolute lymphocyte counts in TMG group (F=5.86, mixed model group effect P=0.02), predominately at 3 months compared with DAC group (0.7±0.6 vs. 2.1±1.0, P=0.0004); however, lymphocyte count was recovered and was back to reference range by 6 months in TMG. There was trend toward more subclinical cytomegalovirus (15% vs. 0%) and BK viremia (17% vs. 0%) in the TMG group, with no differences in the incidence of subclinical Epstein Barr virus viremia (23% vs. 31%) or clinical viral disease. Mean graft function was excellent, and with a minimum follow-up of 6 months, there were no episodes of acute rejection. Conclusion. TMG seems to be a safe alternative induction strategy in patients for SF immunosuppression in pediatric renal transplantation. Extended follow-up and greater enrollment are necessary to fully explore the impact of TMG dosing on viral replication posttransplantation.

Acute rejection episodes are almost inevitable in the face of immunosuppression non-adherence and a known risk factor for developing chronic allograft nephropathy and accelerated graft loss. Daclizumab, a humanized monoclonal antibody directed against the alpha chain of the IL-2 receptor, is an important advance for induction therapy in renal transplant immunosuppression, reducing early acute graft rejection without affecting the tolerability of standard immunosuppression, for both steroid-based and steroid-free immunosuppressive protocols, in children and adults. In the absence of depot immunosuppression for maintenance therapy, we explored extended daclizumab therapy as temporary maintenance immunosuppression for acute rejection prophylaxis in two patients with recalcitrant immunosuppression non-adherence. Both patients had prior episodes of aggressive acute rejection associated with their non-adherence but achieved stable and rejection-free renal allograft function with daclizumab monotherapy in the presence of documented non-adherence thus providing an effective bridge for up to 12 months until immunosuppression adherence was re-established with ongoing psychosocial support. This report suggests that daclizumab monotherapy over an extended period of time during the period of non-adherence in the post transplant period could be a rescue modality to avoid immune activation and thereby prevent acute rejection in the face of erratic maintenance immunosuppression.

Bartter's syndrome (BS) is an incurable genetic disease, with variable response to supportive therapy relating to fluid and electrolyte management. Poor control or therapy non-compliance may result in frequent life threatening episodes of dehydration, acidosis and hypokalemia, with resultant adverse effects on patient quality of life (QOL). We report, for the first time, pre-emptive bilateral native nephrectomies and successful renal transplantation, prior to the onset of ESRD, for severe, clinically brittle, neonatal BS, resulting in correction of metabolic abnormalities and excellent graft function. We propose that fragile BS should be considered as a possible indication for early native nephrectomies and pre-emptive renal transplantation, procedures that results in a 'cure' for the underlying disease and significant improvements in patient QOL.