Biomarkers Predicting Treatment-Response in Nephrotic Syndrome of Children: A Systematic Review

Purpose: Nephrotic syndrome (NS) is the most common form of glomerulopathy in children. Most pediatric patients respond to glucocorticosteroid treatment (steroid-sensitive NS, SSNS), while approximately 10–15% will remain unresponsive or later become steroid-resistant. There has been a long-standing effort to find biomarkers that may predict steroid responsiveness.Methods: We systematically reviewed current studies which investigated clinically relevant biomarkers for predicting steroid responsiveness in pediatric NS. We performed a PubMed and EMBASE search to identify eligible articles. We collected data on urinary markers, blood/serum markers (including cellular phenotypes and mRNA expression), genotypes and HLA allele frequency.Results: A total of 659 articles were identified following electronic and manual searches. After reviewing the titles, abstracts, and full texts, 72 eligible articles were finally included. Vitamin D-binding protein (VDBP) seemed to be significantly elevated in SRNS than in SSNS, in both serum and urine specimen, although further validation is required.Conclusions: The present paper narratively illustrates current understandings of potential biomarkers that may help predict steroid responsiveness. Further investigation and collaboration involving a larger number of patients are necessary.

MAPR origins reveal a new class of prokaryotic cytochrome b5 proteins and possible role in eukaryogenesis

The multiple functions of PGRMC1, the archetypal heme-binding eukaryotic MAPR family member, include steroidogenic regulation, membrane trafficking, and steroid responsiveness. The interrelationships between these functions are currently poorly understood. Previous work has shown that different MAPR subclasses were present early in eukaryotic evolution, and that tyrosine phosphorylated residues appeared in the eumetazoan ancestor, coincident with a gastrulation organizer. Here we show that MAPR proteins are related to a newly recognized class of prokaryotic cytochrome-b5 domain proteins. Our first solved structure of this new class exhibits shared MAPR-like folded architecture and heme-binding orientation. We also report that a protein subgroup from Candidate Phyla Radiation (CPR) bacteria shares MAPR-like heme-interacting tyrosines. Our results support bacterial origins for both PGRMC1 and CYP51A, that catalyze the meiosis-associated 14-demethylation of the first sterol lanosterol from yeast to humans. We propose that eukaryotic acquisition of a membrane-trafficking function related to sterol metabolism was associated with the appearance of MAPR genes early in eukaryotic evolution.

Practice patterns and outcomes of repository corticotropin injection (Acthar® Gel) use in childhood nephrotic syndrome: A study of the North American Pediatric Renal Trials and collaborative studies and the Pediatric Nephrology Research Consortium

Objective: We set up a U.S. registry to examine prescription patterns and patient outcomes of repository corticotropin injection (Acthar® Gel) for childhood nephrotic syndrome. Methods: 18 participating U.S. pediatric centers performed retrospective review and prospective observation of patients < 21 years old with nephrotic syndrome treated with Acthar Gel. We captured baseline characteristics, drug regimen and duration, and disease response following treatment. Results: 46 patients, enrolled from 2015 to 2020 were included. 27 (58.7%) were male. 18 patients (39.1%) had a diagnosis of minimal change followed by focal segmental glomerulosclerosis in 16 patients (34.7%). Median age at start of treatment was 12.5 years (IQR 8.5-17.4) compared to 5.3 years at diagnosis (IQR 2.7-10.5 years). 52% were resistant to corticosteroids. The most common Acthar Gel regimen was 80IU twice a week with a median duration of 199 days (IQR 88-365). Among 37 patients with active disease, 18 (49%) were able to achieve partial or complete remission, though all patients that had a positive response were on other immunosuppressants concomitantly. Conclusion: We report the findings of the largest registry cohort of pediatric patients in the U.S. treated with Acthar Gel for clinically challenging cases of nephrotic syndrome. Acthar Gel was successful in inducing remission in approximately half of the patients with active disease at time of treatment. No predictors of response with respect to demographic data, age at start of Acthar Gel therapy, etiology of nephrotic syndrome, presence or absence of comorbidities, or steroid responsiveness was noted.

Topical interferon in recurrent inflammatory macular edema following a cat bite

Introduction: Treating chronic macular edema (CME) post endophthalmitis is a challenge. Use of steroids may reactivate the infection and repeated intravitreal therapy with anti-vascular growth factor inhibitors (Anti-VEGF) puts the patient again at the risk of exacerbation of inflammation or endophthalmitis. We describe a case of CME post traumatic endophthalmitis successfully treated with topical interferon therapy. Case description: A 34-year-old Asian Indian lady with a history of cat bite to her right eye and treated elsewhere as traumatic endophthalmitis with recurrent macular edema, presented to us 1 year after the injury. She had received anti-VEGF injection for same. Her medical history was non-contributory except for close contact with her cat. Therapeutic trials with oral doxycycline followed by oral albendazole with steroids, as well as repeated anti-VEGF therapy failed to prevent recurrence of CME. Patient’s steroid responsiveness and reluctance for injections, made us to opt for a novel topical Interferon therapy. Macular edema resolved in 2 months. Interruption of interferon therapy due to COVID-lock down resulted in recurrence of the CME, which again responded well to interferon monotherapy. Conclusion: Topical interferon may have a role in the treatment of inflammatory macular edema and can serve as a, safer, economical and non-invasive treatment option compared to intravitreal steroids and anti-VEGFs.

Exhaled 15-HETE and thromboxin-B2 are associated with the therapeutic outcome in childhood asthma

Background: Dysregulation of eicosanoids is associated with asthma and a composite of oxylipins, including exhaled LTB4, characterizes childhood asthma. While FeNO has been used as the standard for monitoring steroid responsiveness, the potential utility of eicosanoids in monitoring the therapeutic outcomes remains unclear. We aimed to examine the levels of major eicosanoids representing different metabolic pathways in exhaled breath condensates (EBCs) of children with asthma during exacerbation and after treatment. Methods: Levels of 6 exhaled eicosanoid species in asthmatic children and healthy subjects were evaluated using ELISA. Results: In addition to those previously reported, including LTB4, the levels of exhaled 15-HETE, but not TXB2, showed significant difference between asthmatics (N=318) and healthy controls (N=97), particularly the severe group showed the lowest levels of exhaled 15-HETE. Receiver Operating Characteristic (ROC) analyses revealed similar distinguishing power for the levels of 15-HETE, FEV1 and FeNO, whilethe 15-HETE/LTB4 ratio was significantly lower in subjects with severe asthma (p<0.01). Analysis of asthmatics (N=75) during exacerbation and convalescence showed significant improvement in lung function (FEV1; p<0.001), but not FeNO, concomitant with significantly increased levels of 15-HETE (p<0.001) and reduced levels of TXB2 (p<0.05) after therapy, particularly for those who at the top 30% level during exacerbation. Further, decreased LTB4 and LXA4 at convalescence were noted only in those at the top 30 percentile during exacerbation. Conclusion: The exhaled 15-HETE was found to discriminate childhood asthma while decreased levels of exhaled TXB2 and increased levels of 15-HETE were prominent after treatment.

Cytokine release syndrome in a patient with colorectal cancer following vaccination with BNT162b2 (tozinameran)

We present a case of cytokine release syndrome (CRS) that occurred five days after vaccination with BTN162b2 (tozinameran), an mRNA COVID-19 vaccine, in a patient with colorectal cancer on long-standing anti-PD-1 monotherapy. The CRS was evidenced by raised inflammatory markers, thrombocytopenia, elevated cytokine levels (IFN-y/IL-2R/IL-18/IL-16/IL-10), and steroid responsiveness.

Recent Developments in Tuberculous Meningitis Pathogenesis and Diagnostics

The pathogenesis of Tuberculous meningitis (TBM) is poorly understood, but contemporary molecular biology technologies have allowed for recent improvements in our understanding of TBM. For instance, neutrophils appear to play a significant role in the immunopathogenesis of TBM, and either a paucity or an excess of inflammation can be detrimental in TBM. Further, severity of HIV-associated immunosuppression is an important determinant of inflammatory response; patients with the advanced immunosuppression (CD4+ T-cell count of <150 cells/μL) having higher CSF neutrophils, greater CSF cytokine concentrations and higher mortality than those with CD4+ T-cell counts > 150 cells/μL. Host genetics may also influence outcomes with LT4AH genotype predicting inflammatory phenotype, steroid responsiveness and survival in Vietnamese adults with TBM. Whist in Indonesia, CSF tryptophan level was a predictor of survival, suggesting tryptophan metabolism may be important in TBM pathogenesis. These varying responses mean that we must consider whether a “one-size-fits-all” approach to anti-bacillary or immunomodulatory treatment in TBM is truly the best way forward. Of course, to allow for proper treatment, early and rapid diagnosis of TBM must occur. Diagnosis has always been a challenge but the field of TB diagnosis is evolving, with sensitivities of at least 70% now possible in less than two hours with GeneXpert MTB/Rif Ultra. In addition, advanced molecular techniques such as CRISPR-MTB and metagenomic next generation sequencing may hold promise for TBM diagnosis. Host-based biomarkers and signatures are being further evaluated in childhood and adult TBM as adjunctive biomarkers as even with improved molecular assays, cases are still missed. A better grasp of host and pathogen behaviour may lead to improved diagnostics, targeted immunotherapy, and possibly biomarker-based, patient-specific treatment regimens.