Clinical characteristics and favorable treatment responses of recurrent focal segmental glomerulosclerosis or steroid-resistant nephrotic syndrome in children after kidney transplantation.

BACKGROUND: Recurrence of focal segmental glomerulosclerosis (FSGS) or steroid-resistant nephrotic syndrome (SRNS) after kidney transplant leads to significant morbidity and potentially earlier allograft loss. To date however, reported rates, risk factors and treatment outcomes have varied widely. METHODS: We applied computational phenotypes to a multicenter aggregation of electronic health records data from 7 large pediatric health systems in the USA, to identify recurrence rates, risk factors, and treatment outcomes. We refined the data collection by chart review. RESULTS: From > 7 million patients, we compared children with primary FSGS/SRNS who received a kidney transplant between 2009 and 2020 and who either developed recurrence (n = 67/165; 40.6%) or did not (n = 98/165). Serum albumin level at time of transplant was significantly lower and recipient HLA DR7 presence was significantly higher in the recurrence group. By 36 months post-transplant, complete remission occurred in 58.2% and partial remission in 17.9%. Through 6 years post-transplant, no remission after recurrence was associated with an increased risk of allograft loss over time (p < 0.0001), but any remission showed similar allograft survival and function decline to those with no recurrence. Since treatments were used in non-random fashion, using spline curves and multivariable non-linear analyses, complete + partial remission chance was significantly higher with greater plasmapheresis sessions, CTLA4-Ig doses or LDL-apheresis sessions. Only treatment with anti-CD20, CTLA4-Ig agents, or LDL-apheresis sessions were associated with complete remission. Excluding 25 patients with mutations did not significantly change our results. CONCLUSIONS: Our contemporary high-risk cohort had higher favorable response rates than most prior reports, from combinations of agents.

Acute kidney injury requiring kidney replacement therapy in childhood lupus nephritis: a cohort study of the Pediatric Nephrology Research Consortium and Childhood Arthritis and Rheumatology Research Alliance.

BACKGROUND: Acute kidney injury (AKI) is common in lupus nephritis (LN) and a risk factor for development of chronic kidney disease. In adults with LN, AKI severity correlates with the incidence of kidney failure and patient survival. Data on AKI outcomes in children with LN, particularly those requiring kidney replacement therapy (KRT), are limited. METHODS: A multicenter, retrospective cohort study was performed in children diagnosed between 2010 and 2019 with LN and AKI stage 3 treated with dialysis (AKI stage 3D). Descriptive statistics were used to characterize demographics, clinical data, and kidney biopsy findings; treatment data for LN were not included. Logistic regression was used to examine the association of these variables with kidney failure. RESULTS: Fifty-nine patients (mean age 14.3 years, 84.7% female) were identified. The most common KRT indications were fluid overload (86.4%) and elevated blood urea nitrogen/creatinine (74.6%). Mean follow-up duration was 3.9 ± 2.9 years. AKI recovery without progression to kidney failure occurred in 37.3% of patients. AKI recovery with later progression to kidney failure occurred in 25.4% of patients, and there was no kidney recovery from AKI in 35.6% of patients. Older age, severe (> 50%) tubular atrophy and interstitial fibrosis, and National Institutes of Health (NIH) chronicity index score > 4 on kidney biopsy were associated with kidney failure. CONCLUSIONS: Children with LN and AKI stage 3D have a high long-term risk of kidney failure. Severe tubular atrophy and interstitial fibrosis at the time of AKI, but not AKI duration, are predictive of kidney disease progression. A higher resolution version of the Graphical abstract is available as Supplementary information.

Congenital adrenal calcifications as the first clinical indication of sphingosine lyase insufficiency syndrome: A case report and review of the literature.

Sphingosine Lyase Insufficiency Syndrome (SPLIS) or SGPL1 Deficiency is a newly described entity that is characterized by steroid-resistant nephrotic syndrome, primary adrenal insufficiency, lymphopenia, ichthyosis, and/or endocrine and neurologic abnormalities. The earliest identification of SGPL1 pathogenic variants in association with this syndrome was reported in 2017. Since then, at least 36 patients have been reported with this pediatric syndrome. Here, we report a new patient with SPLIS who had a prenatal finding of adrenal calcifications, congenital nephrotic syndrome, and abnormal newborn screening concerning for Severe Combined Immunodeficiency. We conclude that SPLIS is a clinically recognizable condition with prenatal onset. This case should increase awareness of SPLIS in the differential diagnosis for adrenal calcifications. We present a case on the severe end of the clinical spectrum of SPLIS, and a review of the literature.

New insights into the pathogenesis of Streptococcus pneumoniae-associated hemolytic uremic syndrome.

The purpose of this review is to describe Streptococcus pneumoniae-associated hemolytic uremic syndrome (P-HUS) with emphasis on new insights into the pathophysiology and management over the past 10 years. Even though awareness of this clinico-pathological entity has increased, it likely remains under-recognized. Recent observations indicate that although neuraminidase activity and exposure of the T-antigen are necessary for development of P-HUS, they are not sufficient; activation of the alternate pathway of complement may also contribute. It is unclear, however, whether or not eculizumab and/or plasmapheresis are of value.

Real-world application of the pediatric Glucocorticoid Toxicity Index in childhood-onset lupus.

OBJECTIVES: The pediatric Glucocorticoid Toxicity Index (pGTI) is a new, pediatric-specific tool to quantify glucocorticoid (GC)-related morbidity in children. We evaluated the feasibility and construct validity of retrospective pGTI scoring in patients with pediatric-onset systemic lupus erythematosus (pSLE) and identified risk factors for cumulative toxicity. METHODS: We conducted a retrospective cohort study of patients with pSLE treated with GCs at two pediatric centers (1999-2023). GC exposure was estimated using interval-averaged oral prednisone-equivalent dose and cumulative prednisone-equivalent dose. We scored change in GC toxicity every 6 months (±2) using a modified pGTI including 7 of 10 domains. We calculated the Cumulative Worsening Score (CWS), a continuous summation of toxicity accrued. Mixed effects linear regression was used to identify factors associated with CWS. RESULTS: There were 126 patients with pSLE, including 88 with nephritis, with a median of 6 visits/patient. Nearly half (47 %) experienced toxicity in the Blood Pressure domain. Other common toxicities were mood disturbance (25 %), followed by increased body mass index (BMI), striae, and sleep disturbance (21 % each). Decreased growth velocity was observed in 18 %. There was modest correlation between cumulative GC dose and CWS (rho 0.3; p < 0.01). Greater cumulative toxicity was associated with younger age, elevated BMI, and rituximab use at the time of GC initiation, albeit indications for the latter were not captured. CONCLUSIONS: Patients with pSLE experience a high burden of GC toxicity, particularly related to blood pressure, BMI, sleep, and growth. Standardized, pediatric-specific GC toxicity assessment is feasible in real-world settings and can facilitate evaluation of strategies to reduce morbidity in children requiring chronic GC treatment.

Outcomes in infants with unprovoked venous thromboembolism: A retrospective cohort study.

Background: Although children aged <1 year have a relatively high rate of venous thromboembolism (VTE) compared to older children, most have additional prothrombotic risk factors. Unprovoked VTE is rare, and little is known about this population, particularly the risk of recurrent VTE. Objectives: We aimed to determine the rate of recurrent VTE in infants with prior unprovoked VTE and evaluate long-term, end-organ outcomes for infants with renal and intracranial vein thrombosis. Methods: Infants <1 year of age with an unprovoked VTE between 2003 and 2021 at a single institution were included. Time to recurrent event and anticoagulation duration were summarized using the Kaplan-Meier estimator. Neurologic outcomes were summarized with the pediatric stroke outcome measure for infants with cerebral sinovenous, medullary, or cortical vein thrombosis. Kidney outcomes were summarized with estimated glomerular filtration rates for infants with renal vein thrombosis. Anticoagulation was summarized. Results: Forty infants with intracranial, renal, portal, and extremity VTE met the inclusion criteria and were followed for a median of 4.7 years (IQR, 2.1-8.5). Most VTE events occurred during the first month of life. There was 1 recurrent event in 237 person-years of follow-up (incidence rate, 4 per 1000 [95% CI, 0.6-29.9] person-years). In outpatient follow-up, 40% of infants with intracranial thrombosis met criteria for moderate or severe neurologic outcomes and two-thirds of infants with a prior renal vein thrombosis had abnormal kidney function (estimated glomerular filtration rate < 90 mL/min/1.73 m2). Conclusion: There is a low rate of recurrent VTE but significant end-organ morbidity in infants with unprovoked VTE.

Using a Multi-Institutional Pediatric Learning Health System to Identify Systemic Lupus Erythematosus and Lupus Nephritis: Development and Validation of Computable Phenotypes.

BACKGROUND AND OBJECTIVES: Performing adequately powered clinical trials in pediatric diseases, such as SLE, is challenging. Improved recruitment strategies are needed for identifying patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Electronic health record algorithms were developed and tested to identify children with SLE both with and without lupus nephritis. We used single-center electronic health record data to develop computable phenotypes composed of diagnosis, medication, procedure, and utilization codes. These were evaluated iteratively against a manually assembled database of patients with SLE. The highest-performing phenotypes were then evaluated across institutions in PEDSnet, a national health care systems network of >6.7 million children. Reviewers blinded to case status used standardized forms to review random samples of cases (n=350) and noncases (n=350). RESULTS: Final algorithms consisted of both utilization and diagnostic criteria. For both, utilization criteria included two or more in-person visits with nephrology or rheumatology and ≥60 days follow-up. SLE diagnostic criteria included absence of neonatal lupus, one or more hydroxychloroquine exposures, and either three or more qualifying diagnosis codes separated by ≥30 days or one or more diagnosis codes and one or more kidney biopsy procedure codes. Sensitivity was 100% (95% confidence interval [95% CI], 99 to 100), specificity was 92% (95% CI, 88 to 94), positive predictive value was 91% (95% CI, 87 to 94), and negative predictive value was 100% (95% CI, 99 to 100). Lupus nephritis diagnostic criteria included either three or more qualifying lupus nephritis diagnosis codes (or SLE codes on the same day as glomerular/kidney codes) separated by ≥30 days or one or more SLE diagnosis codes and one or more kidney biopsy procedure codes. Sensitivity was 90% (95% CI, 85 to 94), specificity was 93% (95% CI, 89 to 97), positive predictive value was 94% (95% CI, 89 to 97), and negative predictive value was 90% (95% CI, 84 to 94). Algorithms identified 1508 children with SLE at PEDSnet institutions (537 with lupus nephritis), 809 of whom were seen in the past 12 months. CONCLUSIONS: Electronic health record-based algorithms for SLE and lupus nephritis demonstrated excellent classification accuracy across PEDSnet institutions.

Management of Lupus Nephritis in Children.

Lupus nephritis affects 50-75% of all children with systemic lupus erythematosus with a higher prevalence in Asians. It remains a major contributor to morbidity and mortality in childhood onset lupus. Proliferative lupus nephritis (class III and class IV) warrants aggressive treatment to prevent progression to end stage renal disease. Newer immunosuppressive agents available in the last decade offer more options to treat lupus nephritis. Despite guidelines from professional bodies, there remains a lack of consensus on the treatment of refractory disease and duration of maintenance therapy. We review the treatment options for pediatric patients with lupus nephritis based on studies and published guidelines in the last decade, and highlight opportunities for continued improvement in care.