Eculizumab exposure in children and young adults: indications, practice patterns, and outcomes-a Pediatric Nephrology Research Consortium study.

BACKGROUND: Eculizumab is approved for the treatment of atypical hemolytic uremic syndrome (aHUS). Its use off-label is frequently reported. The aim of this study was to describe the broader use and outcomes of a cohort of pediatric patients exposed to eculizumab. METHODS: A retrospective, cohort analysis was performed on the clinical and biomarker characteristics of eculizumab-exposed patients < 25 years of age seen across 21 centers of the Pediatric Nephrology Research Consortium. Patients were included if they received at least one dose of eculizumab between 2008 and 2015. Traditional summary statistics were applied to demographic and clinical data. RESULTS: A total of 152 patients were identified, mean age 9.1 (+/-6.8) years. Eculizumab was used "off-label" in 44% of cases. The most common diagnoses were aHUS (47.4%), Shiga toxin-producing Escherichia coli HUS (12%), unspecified thrombotic microangiopathies (9%), and glomerulonephritis (9%). Genetic testing was available for 60% of patients; 20% had gene variants. Dosing regimens were variable. Kidney outcomes tended to vary according to diagnosis. Infectious adverse events were the most common adverse event (33.5%). No cases of meningitis were reported. Nine patients died of noninfectious causes while on therapy. CONCLUSIONS: This multi-center retrospective cohort analysis indicates that a significant number of children and young adults are being exposed to C5 blockade for off-label indications. Dosing schedules were highly variable, limiting outcome conclusions. Attributable adverse events appeared to be low. Cohort mortality (6.6%) was not insignificant. Prospective studies in homogenous disease cohorts are needed to support the role of C5 blockade in kidney outcomes.

Trends in Living Donation by Race and Ethnicity Among Children With End-stage Renal Disease in the United States, 1995-2015.

BACKGROUND: Living donor kidney transplants have declined among adults with end-stage renal disease (ESRD), with increases in racial/ethnic disparities over time. Secular trends in racial/ethnic disparities in living donor kidney transplantation have not been well studied in children. METHODS: Using multivariable Cox modeling, we examined changes in living donor kidney transplant rates over time and probability of receiving living donor kidney transplantation within 2 years of incident ESRD by race/ethnicity among 19 772 children in the US Renal Data System, 1995-2015. We also examined racial/ethnic concordance between donors and recipients. RESULTS: Overall, living donor kidney transplant rates declined by 3% annually since 1995 for all racial/ethnic groups except Asians for whom living donor kidney transplant rates remained stable; however, disparities persist. Compared with non-Hispanic white children, Hispanics were 42% less likely (adjusted hazard ratio: 0.58; 95% confidence interval: 0.49-0.67), Asians 39% less likely (0.61; 0.47-0.79), and blacks 66% less likely (0.34; 0.28-0.42) to receive living kidney donor transplantation within 2 years, even when accounting for deceased donor transplantation as a competing risk. Additionally, while 95% of non-Hispanic white children had non-Hispanic white donors, only 56% of Asian recipients had Asian donors (P < 0.001). Asian recipients were more likely to have nonrelated donors (P < 0.001). CONCLUSIONS: There are ongoing declines in living donation for children with ESRD for uncertain reasons, and minority populations experience significantly reduced access to timely living donor transplant, even when accounting for changes in deceased donation and donor-recipient relationships.

Higher eGFR at Dialysis Initiation Is Not Associated with a Survival Benefit in Children.

BACKGROUND: Study findings suggest that initiating dialysis at a higher eGFR level in adults with ESRD does not improve survival. It is less clear whether starting dialysis at a higher eGFR is associated with a survival benefit in children with CKD. METHODS: To investigate this issue, we performed a retrospective cohort study of pediatric patients aged 1-18 years who, according to the US Renal Data System, started dialysis between 1995 and 2015. The primary predictor was eGFR at the time of dialysis initiation, categorized as higher (eGFR>10 ml/min per 1.73 m2) versus lower eGFR (eGFR≤10 ml/min per 1.73 m2). RESULTS: Of 15,170 children, 4327 (29%) had a higher eGFR (median eGFR, 12.8 ml/min per 1.73 m2) at dialysis initiation. Compared with children with a lower eGFR (median eGFR, 6.5 ml/min per 1.73 m2), those with a higher eGFR at dialysis initiation were more often white, girls, underweight or obese, and more likely to have GN as the cause of ESRD. The risk of death was 1.36 times higher (95% confidence interval, 1.24 to 1.50) among children with a higher (versus lower) eGFR at dialysis initiation. The association between timing of dialysis and survival differed by treatment modality-hemodialysis versus peritoneal dialysis (P<0.001 for interaction)-and was stronger among children initially treated with hemodialysis (hazard ratio, 1.56, 95% confidence interval, 1.39 to 1.75; versus hazard ratio, 1.07, 95% confidence interval, 0.91 to 1.25; respectively). CONCLUSIONS: In children with ESRD, a higher eGFR at dialysis initiation is associated with lower survival, particularly among children whose initial treatment modality is hemodialysis.

A 27-Month-Old Boy with Polyuria and Polydipsia.

Psychogenic polydipsia is a well-described phenomenon in those with a diagnosed psychiatric disorder such as schizophrenia and anxiety disorders. Primary polydipsia is differentiated from psychogenic polydipsia by the lack of a clear psychotic disturbance. We present a case of a 27-month-old boy who presented with polyuria and polydipsia. Laboratory studies, imaging, and an observed water deprivation test were consistent with primary polydipsia. Polydipsia resolved after family limited his fluid intake and began replacing water drinking with other transition objects and behaviors for self-soothing. This case highlights the importance of water deprivation testing to differentiate between causes of polyuria, thereby avoiding misdiagnosis and iatrogenic hyponatremia. Secondly, primary polydipsia can result during the normal stages of child development without overt psychiatric disturbances.

Effect of BMI on allograft function and survival in pediatric renal transplant recipients.

OBJECTIVE: To determine whether pre-transplant body mass index (BMI) affects renal allograft function and survival in pediatric renal transplant recipients. STUDY DESIGN: This is a retrospective cohort study using the Organ Procurement and Transplantation Network data from 2000 to 2013 to compare time to total allograft loss (allograft failure or death), prevalence of delayed graft function, prevalence of acute rejection, and estimated glomerular filtration rate (eGFR) post-transplant in pediatric renal transplant recipients categorized by BMI z-score. RESULTS: A total of 8804 kidney transplant recipients met our inclusion criteria, and of those, 6% were underweight, 14% were overweight, and 17% were obese pre-transplant. The adjusted hazard ratio (HR) for allograft failure was significantly higher for obese recipients compared to normal weight recipients (HR 1.25, 95% CI 1.1, 1.42); for every 1 point increase in BMI z-score, there was a 7% increased hazard of allograft failure (HR 1.07; 95% CI 1.03-1.1, p < 0.001). The prevalence of delayed graft function and acute rejection increased with higher BMI z-score category; however, this difference did not reach statistical significance. eGFR at 1 and 5 years post-transplant decreased with higher BMI z-score although it was only statistically significant at 1 year. CONCLUSIONS: Obesity is prevalent in pediatric renal transplant recipients, and obese, but not overweight or underweight, pediatric renal transplant recipients have an increased risk of allograft failure. Implementation of effective obesity interventions in pediatric renal transplant recipients is of critical importance to improve longevity of the renal allograft.

Use of the Kidney Failure Risk Equation to Determine the Risk of Progression to End-stage Renal Disease in Children With Chronic Kidney Disease.

Importance: The kidney failure risk equation (KFRE) has been shown to accurately estimate progression to kidney failure in adults with chronic kidney disease (CKD). Use of the KFRE in children with CKD, if accurate, would help to optimize planning for end-stage renal disease (ESRD) care. Objective: To determine whether the KFRE adequately discriminates the risk of ESRD in children with CKD. Design, Setting, and Participants: This retrospective cohort study included 603 children with an estimated glomerular filtration rate of less than 60 mL/min/1.73 m2 in the Chronic Kidney Disease in Children study, a national multicenter observational study. Data were collected from January 1, 2005, through July 31, 2013, and analyzed from September 30, 2016, through September 8, 2017. Exposures: The primary predictive factors were the 4-variable (age, sex, bedside Schwartz estimated glomerular filtration rate, and ratio of albumin to creatinine levels) and 8-variable (4 variables plus serum calcium, phosphate, bicarbonate, and albumin levels) KFREs, which provide 1-, 2-, and 5-year estimates of the risk of progression to ESRD. Main Outcomes and Measures: Time to ESRD. The Cox proportional hazards model was used to examine the association between the KFRE score and time to ESRD. C statistics were used to discriminate ESRD risk by the KFRE, with a value of greater than 0.80 indicating strong discrimination. Results: Of the 603 children included in the study, 378 were boys (62.7%) and 225 were girls (37.3%); median age at study entry was 12 years (interquartile range, 8-15 years). Median estimated glomerular filtration rate was 44 mL/min/1.73 m2. Four hundred fifty-seven participants (75.8%) had a nonglomerular cause of CKD. Median observation time was 3.8 years (interquartile range, 1.7-6.2 years); 144 (23.9%) developed ESRD within 5 years of enrollment. The 4-variable KFRE scores discriminated risk of ESRD, with C statistics of 0.90, 0.86, and 0.81 for the 1-, 2-, and 5-year risk scores, respectively. Results were similar using the 8-variable equation. Conclusions and Relevance: The KFRE is a simple tool that provides excellent discrimination of the risk of ESRD. Results suggest that the KFRE could be incorporated into the clinical care of children with CKD to aid in anticipatory guidance, timing of referral for transplant evaluation, and planning for dialysis access.

Comparable Survival of En Bloc versus Standard Donor Kidney Transplants in Children.

OBJECTIVE: To determine whether renal transplantation survival is similar in children receiving pediatric en bloc kidneys compared with those receiving standard deceased donor kidneys. STUDY DESIGN: We compared time to allograft failure and estimated glomerular filtration rate (eGFR) in pediatric recipients of en bloc and standard criteria deceased donor renal transplants using Organ Procurement and Transplantation Network data for 2000-2013. Cox regression analysis was used to compare time to allograft failure, and the Student t test was used to compare eGFR. RESULTS: A total of 6882 recipients met the study inclusion criteria; 1.8% received an en bloc transplant. The adjusted hazard for allograft failure was similar for recipients of en bloc kidneys compared with standard criteria kidneys (hazard ratio, 1.15; 95% CI, 0.83-1.59; P = .41). The median wait time for transplantation was significantly shorter for recipients of en bloc kidneys (157 days vs 208 days; P = .03). Moreover, eGFR was superior for recipients of en bloc kidneys up to 5 years post-transplantation. CONCLUSION: Transplantation of en bloc pediatric kidneys should be considered a viable option for pediatric recipients and may afford unique benefits by reducing wait times and promoting preservation of graft function.

Response to childhood immunizations in congenital nephrotic syndrome.

Infections are a leading cause of morbidity in children following transplantation. It is therefore imperative to ensure that children are immunized before a transplant. Contrary to this recommendation, it has long been suggested that children with congenital nephrotic syndrome (CNS) not receive immunizations due to their perceived lack of response. We report a child with CNS who was immunized before transplantation per the routine pediatric immunization protocol and responded appropriately. The intent of this report is to encourage health care providers to immunize children with CNS, as the practice of withholding immunizations in these patients may have adverse health implications.

Gross hematuria as a sign of acute rejection.

In the contemporary era of potent immunosuppressive regimens, previously encountered signs of renal allograft rejection such as fever and hematuria are rarely encountered. We report a teenager with severe recurrent acute humoral and cellular rejection whose presenting feature was gross hematuria with the presence of blood clots in the urine. We want to highlight that severe rejection even in the setting of modern immunosuppressive drugs can present as gross hematuria. Contrary to conventional wisdom that gross hematuria with the presence of blood clots in the urine is indicative of pathology in the renal collecting system, a parenchymal disease process should also be considered in renal transplant recipients.

The brain processing of scratching.

Neuroimaging studies have examined the neural networks activated by pruritus but not its behavioral response, scratching. In this study, we examine the central sensory effects of scratching using blood oxygen level-dependent functional magnetic resonance imaging (fMRI) in 13 healthy human subjects. Subjects underwent functional imaging during scratching of the right lower leg. Scratching stimulus was started 60 seconds after initiation of fMRI acquisition and was cycled between 30-second duration applications of scratching and 30-second duration applications of no stimuli. Our results show that repetitive scratching induces robust bilateral activation of the secondary somatosensory cortex, insular cortex, prefrontal cortex, inferior parietal lobe, and cerebellum. In addition, we show that the same stimulus results in robust deactivation of the anterior and posterior cingulate cortices. This study demonstrates brain areas (motor, sensory, and non-sensory) activated and deactivated by repetitive scratching. Future studies that investigate the central effects of scratching in chronic itch conditions will be of high clinical relevance.