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Atypical hemolytic uremic syndrome (aHUS) is a rare, possibly life-threatening disease characterized by platelet activation, hemolysis and thrombotic microangiopathy (TMA) leading to renal and other end-organ damage. We originally conducted two phase 2 studies (26 weeks and 1 year) evaluating eculizumab, a terminal complement inhibitor, in patients with progressing TMA (trial 1) and those with long duration of aHUS and chronic kidney disease (trial 2). The current analysis assessed outcomes after 2 years (median eculizumab exposure 100 and 114 weeks, respectively). At all scheduled time points, eculizumab inhibited terminal complement activity. In trial 1 with 17 patients, the platelet count was significantly improved from baseline, and hematologic normalization was achieved in 13 patients at week 26, and in 15 patients at both 1 and 2 years. The estimated glomerular filtration rate (eGFR) was significantly improved compared with baseline and year 1. In trial 2 with 20 patients, TMA event-free status was achieved by 16 patients at week 26, 17 patients at year 1, and 19 patients at year 2. Criteria for hematologic normalization were met by 18 patients at each time point. Improvement of 15 ml/min per 1.73 m2 or more in eGFR was achieved by 1 patient at week 26, 3 patients at 1 year, and 8 patients at 2 years. The mean change in eGFR was not significant compared with baseline, week 26, or year 1. Eculizumab was well tolerated, with no new safety concerns or meningococcal infections. Thus, a 2-year analysis found that the earlier clinical benefits achieved by eculizumab treatment of aHUS were maintained at 2 years of follow-up.

Background There are limited long-term outcome data in eculizumab-treated patients with atypical hemolytic uremic syndrome (aHUS). We report final results from the largest prospective, observational, multicenter study of patients with aHUS treated with eculizumab. Methods Patients with aHUS who participated in any of five parent eculizumab trials and received at least one eculizumab infusion were eligible for enrollment in a long-term follow-up study. Rates of thrombotic microangiopathy (TMA) manifestations off versus on eculizumab were evaluated. Additional endpoints included change from baseline estimated glomerular filtration rate (eGFR), long-term renal outcomes, and serious targeted treatment-emergent adverse events. Results Among 93 patients (0–80 years of age), 51 (55%) remained on eculizumab and 42 (45%) discontinued; for those who discontinued, 21 (50%) reinitiated therapy. Patients who reinitiated eculizumab had similar baseline clinical characteristics to patients who remained on eculizumab, with higher likelihood of genetic/autoimmune complement abnormalities, more prior TMAs, and longer disease course versus those who did not reinitiate. Mean eGFR improved rapidly and remained stable for up to 6 years on eculizumab. In patients who discontinued, there was a trend toward decreasing renal function over time from discontinuation. Additionally, off-treatment TMA manifestation rates were higher in those aged < 18 years at diagnosis, with identified genetic/autoimmune complement abnormalities, or history of multiple TMAs prior to eculizumab initiation. The safety profile was consistent with previous studies. Three definite and one possible meningococcal infections related to eculizumab were reported and resolved with treatment. Three deaths unrelated to eculizumab were reported. Conclusions The current study confirms the efficacy and safety of eculizumab in aHUS, particularly with regard to long-term renal function and TMA events. Pediatric age at disease onset and presence of genetic or autoimmune complement abnormalities are risk factors for TMA events off treatment. Overall, patients who discontinue eculizumab may be at risk for additional TMA manifestations and renal function decreases. Discontinuation of eculizumab, with careful monitoring, is an option in select patients with consideration of patient preference, organ function normalization, and risk factors for relapse, including mutational analysis, age of onset, and history of multiple TMA episodes. Trial registration ClinicalTrials.gov NCT01522170 , January 31, 2012.

Corticosteroids have been used to treat childhood nephrotic syndrome for more than 50 years but a minority of patients, especially those with focal segmental glomerulosclerosis, are resistant to this treatment, This Review summarizes the currently available treatments for both steroid-sensitive and steroid-resistant childhood nephrotic syndrome, and discusses selected novel pathways in podocytes that could be targeted for the development of next-generation treatments for children with this syndrome. The introduction of corticosteroids more than 50 years ago dramatically improved the prognosis of children with nephrotic syndrome. Corticosteroids remain the standard initial treatment for children with this disease, but a considerable proportion of patients do not respond and are therefore at risk of progressing to end-stage renal disease. Because of this risk, new therapeutic strategies are needed for steroid-resistant nephrotic syndrome. These strategies have historically focused on identifying effective alternative immunosuppressive agents, such as ciclosporin and tacrolimus, yet evidence now indicates that nephrotic syndrome results from podocyte dysfunction. Even conventional immunosuppressive agents, such as glucocorticoids and ciclosporin, directly affect podocyte structure and function, challenging the 'immune theory' of the pathogenesis of childhood nephrotic syndrome in which disease is caused by T cells. This Review summarizes the currently available treatments for childhood nephrotic syndrome, and discusses selected novel pathways in podocytes that could be targeted for the development of next-generation treatments for children with this syndrome. Key Points Corticosteroids have been used to treat childhood nephrotic syndrome for more than 50 years but a minority of patients, especially those with focal segmental glomerulosclerosis, are resistant to this treatment Evidence now suggests that childhood nephrotic syndrome is attributable to podocyte dysfunction; many medications used to treat childhood nephrotic syndrome target the immune system, but also directly affect podocytes Several currently available agents developed for other diseases, such as diabetes, are now being considered for treatment of steroid-resistant childhood nephrotic syndrome Ongoing research has identified a number of pathways occuring in podocytes that may be potential targets for future therapies to treat steroid-resistant childhood nephrotic syndrome

Serial kidney biopsy for repeat evaluation and monitoring of lupus nephritis (LN) in childhood-onset Systemic Lupus Erythematosus (cSLE) remains challenging, thus non-invasive biomarkers are needed. Here, we evaluate the performance of ten urine protein markers of diverse nature including cytokines, chemokines, and adhesion molecules in distinguishing disease activity in cSLE. Eighty-four pediatric patients meeting ≥4 ACR criteria for SLE were prospectively enrolled for urine assay of 10 protein markers normalized to urine creatinine, namely ALCAM, cystatin-C, hemopexin, KIM-1, MCP-1, NGAL, PF-4, Timp-1, TWEAK, and VCAM-1 by ELISA. Samples from active renal (LN) and active non-renal SLE patients were obtained prior to onset/escalation of immunosuppression. SLE disease activity was evaluated using SLEDAI-2000. 59 patients had clinically-active SLE (SLEDAI score ≥4 or having a flare), of whom 29 patients (34.5%) were classified as active renal, and 30 patients (35.7%) were active non-renal. Twenty-five healthy subjects were recruited as controls. Urine concentrations of ALCAM, KIM-1, PF4 and VCAM-1 were significantly increased in active LN patients versus active non-renal SLE, inactive SLE and healthy controls. Five urine proteins differed significantly between 2 (hemopexin, NGAL, MCP1) or 3 (Cystatin-C, TWEAK) groups only, with the highest levels detected in active LN patients. Urine ALCAM, VCAM-1, PF4 and hemopexin correlated best with total SLEDAI as well as renal-SLEDAI scores (p < 0.05). Urine ALCAM, VCAM-1 and hemopexin outperformed conventional laboratory measures (anti-dsDNA, complement C3 and C4) in identifying concurrent SLE disease activity among patients (AUCs 0.75, 0.81, 0.81 respectively), while urine ALCAM, VCAM-1 and PF4 were the best discriminators of renal disease activity in cSLE (AUCs 0.83, 0.88, 0.78 respectively), surpassing conventional biomarkers, including proteinuria. Unsupervised Bayesian network analysis based on conditional probabilities re-affirmed urine ALCAM as being most predictive of active LN in cSLE patients. Urinary ALCAM, PF4, and VCAM-1 are potential biomarkers for predicting kidney disease activity in cSLE and hold potential as surrogate markers of nephritis flares in these patients.

Purpose Autosomal recessive polycystic kidney disease (ARPKD) is a hereditary condition characterized by massive kidney enlargement and developmental liver defects. Potential consequences during childhood include the need for kidney replacement therapy (KRT). We report the design of 2 ongoing clinical trials (Study 204, Study 307) to evaluate safety, tolerability, and efficacy of tolvaptan in children with ARPKD. Methods Both trials are of multinational, multicenter, open-label design. Age range at enrollment is 28 days to < 12 weeks in Study 204 and 28 days to < 18 years in Study 307. Subjects in both studies must have a clinical diagnosis of ARPKD, and those in Study 204 must additionally have signs indicative of risk of rapid progression to KRT, namely, all of: nephromegaly, multiple kidney cysts or increased kidney echogenicity suggesting microcysts, and oligohydramnios or anhydramnios. Target enrollment is 20 subjects for Study 204 and ≥ 10 subjects for Study 307. Results Follow-up is 24 months in Study 204 (with optional additional treatment up to 36 months) and 18 months in Study 307. Outcomes include safety, tolerability, change in kidney function, and percentage of subjects requiring KRT relative to historical data. Regular safety assessments monitor for possible adverse effects of treatment on parameters such as liver function, kidney function, fluid balance, electrolyte levels, and growth trajectory, with increased frequency of monitoring following tolvaptan initiation or dose escalation. Conclusions These trials will provide data on tolvaptan safety and efficacy in a population without disease-specific treatment options. Trial registration Study 204: EudraCT 2020–005991-36; Study 307: EudraCT 2020–005992-10.

Background The outbreak of severe acute respiratory syndrome coronavirus 2 has had an enormous impact on global health. Vaccination remains one of the most effective interventions for disease prevention. Clinically significant vaccine side effects are uncommon, though autoimmune-mediated disease occurs in a small percentage of vaccine recipients. Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease that is associated with significant morbidity and mortality. Childhood-onset SLE tends to have more severe disease manifestations than adult-onset SLE. In adults, there are a few reported cases of SLE developing soon after coronavirus disease 2019 (COVID-19) mRNA vaccination. Case presentation A 14-year-old previously healthy male developed laboratory and clinical evidence of SLE, including maculopapular malar rash, arthritis, pleuritic chest pain, and class V (membranous) lupus nephritis, 2 days after his third dose of the Pfizer-BioNTech COVID-19 vaccine. The patient’s symptoms improved after initiation of prednisone and mycophenolate mofetil. We also summarize eleven prior case reports describing SLE after COVID-19 vaccine in adults. Conclusion To our knowledge, this is the first reported pediatric patient with new onset SLE following COVID-19 mRNA vaccination. While potential mechanistic links exist between COVID-19 vaccination and SLE development, additional studies are necessary to elucidate the exact nature of this relationship.

Background Atypical hemolytic uremic syndrome (aHUS) is a rare, genetically-mediated systemic disease most often caused by chronic, uncontrolled complement activation that leads to systemic thrombotic microangiopathy (TMA) and renal and other end-organ damage. Methods The global aHUS Registry, initiated in April 2012, is an observational, noninterventional, multicenter registry designed to collect demographic characteristics, medical and disease history, treatment effectiveness and safety outcomes data for aHUS patients. The global aHUS Registry will operate for a minimum of 5 years of follow-up. Enrollment is open to all patients with a clinical diagnosis of aHUS, with no requirement for identified complement gene mutations, polymorphisms or autoantibodies or particular type of therapy/management. Results As of September 30, 2014, 516 patients from 16 countries were enrolled. At enrollment, 315 (61.0 %) were adults (≥18 years) and 201 (39.0 %) were <18 years of age. Mean (standard deviation [SD]) age at diagnosis was 22.7 (20.5) years. Nineteen percent of patients had a family history of aHUS, 60.3 % had received plasma exchange/plasma infusion, 59.5 % had a history of dialysis, and 19.6 % had received ≥1 kidney transplant. Overall, 305 patients (59.1 %) have received eculizumab. Conclusions As enrollment and follow-up proceed, the global aHUS Registry is expected to yield valuable baseline, natural history, medical outcomes, treatment effectiveness and safety data from a diverse population of patients with aHUS. Trial registration US National Institutes of Health www.ClinicalTrials.gov Identifier NCT01522183 . Registered January 18, 2012.

Background Home monitoring of urine protein is a critical component of disease management in childhood nephrotic syndrome. We describe the development of a novel mobile application, UrApp – Nephrotic Syndrome Manager, to aid disease monitoring. Methods UrApp was iteratively developed by a panel of two pediatric nephrologists and three research engineers from May 2017 to October 2018 for Apple iPhones. App features were devised by this expert panel to support urine monitoring and other home care tasks. Each feature and user-app interface element was systematically reviewed by the panel and iteratively redesigned to remove anticipated use issues. The app prototype was then refined based on two rounds of usability testing and semi-structured user interviews with a total of 20 caregivers and adolescent patients. The analytic function of UrApp in providing a camera read of the urine test strip was compared to a standard urinalysis machine using 88 patient urine samples and three iPhones, model versions 6S and 7. Exact agreement and weighted kappa were calculated between the UrApp and urinalysis machine reads. Results The final UrApp features include: camera read of a urine test strip; analysis of urine protein trends and alerts for new disease relapse/remission; transmission of urine protein results to providers; education materials; and medication reminders. During the second round of UrApp usability testing, all users were able to perform each of the functions without error and all perceived UrApp to be helpful and indicated that they would use UrApp. UrApp camera results had 97% exact agreement and an overall weighted kappa value of 0.91 (95% CI, 0.85–0.97) compared with standard urinalysis machine interpretation. Conclusions UrApp was specifically designed to support patients and families living with nephrotic syndrome by supporting disease monitoring and home management tasks. The technically innovative feature that makes this possible is the use of a smartphone camera to read the urine test strip. This novel tool has the potential to improve disease monitoring and reduce management burden.

Background Nephrotic syndrome represents a condition in pediatric nephrology typified by a relapsing and remitting course, proteinuria and the presence of edema. The PROMIS measures have previously been studied and validated in cross-sectional studies of children with nephrotic syndrome. This study was designed to longitudinally validate the PROMIS measures in pediatric nephrotic syndrome. Methods One hundred twenty seven children with nephrotic syndrome between the ages of 8 and 17 years participated in this prospective cohort study. Patients completed a baseline assessment while their nephrotic syndrome was active, a follow-up assessment at the time of their first complete proteinuria remission or study month 3 if no remission occurred, and a final assessment at study month 12. Participants completed six PROMIS measures (Mobility, Fatigue, Pain Interference, Depressive Symptoms, Anxiety, and Peer Relationships), the PedsQL version 4.0, and two global assessment of change items. Results Disease status was classified at each assessment: nephrotic syndrome active in 100% at baseline, 33% at month 3, and 46% at month 12. The PROMIS domains of Mobility, Fatigue, Pain Interference, Depressive Symptoms, and Anxiety each showed a significant overall improvement over time ( p  < 0.001). When the PROMIS measures were compared to the patients’ global assessment of change, the domains of Mobility, Fatigue, Pain Interference, and Anxiety consistently changed in an expected fashion. With the exception of Pain Interference, change in PROMIS domain scores did not correlate with changes in disease activity. PROMIS domain scores were moderately correlated with analogous PedsQL domain scores. Conclusion This study demonstrates that the PROMIS Mobility, Fatigue, Pain Interference, and Anxiety domains are sensitive to self-reported changes in disease and overall health status over time in children with nephrotic syndrome. The lack of significant anchoring to clinically defined nephrotic syndrome disease active and remission status may highlight an opportunity to improve the measurement of HRQOL in children with nephrotic syndrome through the development of a nephrotic syndrome disease-specific HRQOL measure.

Background Growth impairment remains common in children with chronic kidney disease (CKD). Available literature indicates low level of recombinant human growth hormone (rhGH) utilization in short children with CKD. Despite efforts at consensus guidelines, lack of high-level evidence continues to complicate rhGH therapy decision-making and the level of practice variability in rhGH treatment by pediatric nephrologists is unknown. Methods Cross-sectional online survey electronically distributed to pediatric nephrologists through the Midwest Pediatric Nephrology Consortium and American Society of Pediatric Nephrology. Results Seventy three pediatric nephrologists completed the survey. While the majority (52.1%) rarely involve endocrinology in rhGH management, 26.8% reported that endocrinology managed most aspects of rhGH treatment in their centers. The majority of centers (68.5%) have a dedicated renal dietitian, but 20.6% reported the nephrologist as the primary source of nutritional support for children with CKD. Children with growth failure did not receive rhGH most commonly because of family refusal. Differences in initial work-up for rhGH therapy include variable use of bone age (95%), thyroid function (58%), insulin-like growth factor-1 (40%), hip/knee X-ray (36%), and ophthalmologic evaluation (7%). Most pediatric nephrologists (95%) believe that rhGH treatment improves quality of life, but only 24% believe that it improves physical function; 44% indicated that rhGH improves lean body mass. Conclusions There is substantial variation in pediatric nephrology practice in addressing short stature and rhGH utilization in children with CKD. Hence, there may be opportunities to standardize care to study and improve growth outcomes in short children with CKD.