Leflunomide as adjunct therapy for BK viremia management in pediatric kidney transplant recipients.

BACKGROUND: BK viremia after kidney transplantation (KT) poses significant risk for BK virus-associated nephropathy and impacts graft survival. Conventional treatment involves reduction of immunosuppression, which in turn may increase risk for rejection. To address this dilemma, use of anti-viral therapy with immunosuppressive properties such as leflunomide is an attractive option. METHODS: We performed a multi-center, retrospective chart review to report tolerability and effectiveness of leflunomide use for the eradication of BK viremia and prevention of BK virus-associated nephropathy in pediatric KT recipients. RESULTS: Seventy patients prescribed leflunomide were included and were followed up from initiation until 1 year following leflunomide completion. BK viremia was eradicated in 64 (91.4%) patients including 8 of 11 with nephropathy (BKVN) on initial biopsy. Reduced anti-proliferative medication (AP) dosing was not associated with increase in biopsy proven rejection (BPAR). However, complete discontinuation of AP during leflunomide therapy was associated with increase in BPAR in uni- and multivariate logistic regression, as was targeted reduction in calcineurin inhibitor (CNI) trough goals. One graft was lost to BKVN. There was no significant association found between time to BK eradication and leflunomide trough concentration, mycophenolate dose reduction, or steroid use (univariate logistic regression). Few leflunomide adverse drug reactions (ADR) were reported (most commonly: gastrointestinal, hematologic). CONCLUSION: Leflunomide is a promising adjunctive treatment to immunosuppression reduction for BK virus eradication with minimal ADR. AP reduction, not discontinuation, and judicious reduction in CNI trough goals with close monitoring, is a promising strategy for treatment of BK viremia with concomitant use of leflunomide therapy.

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.

Omentectomy reduces the need for peritoneal dialysis catheter revision in children: a study from the Pediatric Nephrology Research Consortium.

BACKGROUND: There are no multi-center studies examining omentectomy and peritoneal dialysis (PD) catheter revision in the pediatric dialysis population. METHODS: We performed a retrospective study at eight centers within the Pediatric Nephrology Research Consortium (PNRC). Data review included all incident tunneled PD catheters placed between 1/1/2011 and 12/31/2016 in pediatric stage 5 chronic kidney disease (CKD 5) patients. The primary outcome was the need for catheter revision and/or replacement. Multivariable logistic regression was performed to evaluate predictors for catheter revision/replacement. RESULTS: Data from 184 children (62.5% male; median age 7.4 years) were analyzed. Omentectomy was completed in 63.6% (n = 117). Revision/replacement occurred in 34.2% (n = 63); median time to revision/replacement was 38.5 days after insertion. PD catheter revision/replacement catheter occurred in 23.9% who underwent omentectomy versus 52.2% without omentectomy (p = 0.0005). Children ≥ 6 years at the time of catheter insertion experienced fewer revisions/replacements (18.2% age ≥ 6 vs. 56.5% age < 6 years, p <0.001). After adjusting for covariates, omentectomy reduced the need for revision by 63%; revision was 3.66 times more likely in those < 6 years of age. CONCLUSIONS: This multi-center study demonstrates that omentectomy at the time of PD catheter insertion in pediatric patients is strongly associated with reduced likelihood of PD catheter revision. Omentectomy should be considered at the time of PD catheter insertion, especially in young children who are at high risk for PD catheter malfunction. A higher resolution version of the Graphical abstract is available as Supplementary information.

The Search for Biomarkers to Aid in Diagnosis, Differentiation, and Prognosis of Childhood Idiopathic Nephrotic Syndrome.

Identification of genes associated with childhood-onset nephrotic syndrome has significantly advanced our understanding of the pathogenesis of this complex disease over the past two decades, however the precise etiology in many cases remains unclear. At this time, we still rely on invasive kidney biopsy to determine the underlying cause of nephrotic syndrome in adults. In children, response to steroid therapy has been shown to be the best indicator of prognosis, and therefore all children are treated initially with corticosteroids. Because this strategy exposes a large number of children to the toxicities of steroids without providing any benefit, many researchers have sought to find a marker that could predict a patient's response to steroids at the time of diagnosis. Additionally, the identification of such a marker could provide prognostic information about a patient's response to medications, progression to end stage renal disease, and risk of disease recurrence following transplantation. Major advances have been made in understanding how genetic biomarkers can be used to predict a patient's response to therapies and disease course, especially after transplantation. Research attempting to identify urine- and serum-based biomarkers which could be used for the diagnosis, differentiation, and prognosis of nephrotic syndrome has become an area of emphasis. In this review, we explore the most exciting biomarkers and their potential clinical applications.

Cross-platform single cell analysis of kidney development shows stromal cells express Gdnf.

The developing kidney provides a useful model for study of the principles of organogenesis. In this report we use three independent platforms, Drop-Seq, Chromium 10x Genomics and Fluidigm C1, to carry out single cell RNA-Seq (scRNA-Seq) analysis of the E14.5 mouse kidney. Using the software AltAnalyze, in conjunction with the unsupervised approach ICGS, we were unable to identify and confirm the presence of 16 distinct cell populations during this stage of active nephrogenesis. Using a novel integrative supervised computational strategy, we were able to successfully harmonize and compare the cell profiles across all three technological platforms. Analysis of possible cross compartment receptor/ligand interactions identified the nephrogenic zone stroma as a source of GDNF. This was unexpected because the cap mesenchyme nephron progenitors had been thought to be the sole source of GDNF, which is a key driver of branching morphogenesis of the collecting duct system. The expression of Gdnf by stromal cells was validated in several ways, including Gdnf in situ hybridization combined with immunohistochemistry for SIX2, and marker of nephron progenitors, and MEIS1, a marker of stromal cells. Finally, the single cell gene expression profiles generated in this study confirmed and extended previous work showing the presence of multilineage priming during kidney development. Nephron progenitors showed stochastic expression of genes associated with multiple potential differentiation lineages.

Kruppel-like factor 5 (KLF5) is critical for conferring uterine receptivity to implantation.

A blastocyst will implant only when the uterus becomes receptive. Following attachment, luminal epithelial cells undergo degeneration at the site of the blastocyst. Although many genes critical for uterine receptivity are primarily regulated by ovarian hormones, Kruppel-like factor 5 (KLF5), a zinc finger-containing transcription factor, is persistently expressed in epithelial cells independently of ovarian hormones. Loss of uterine Klf5 causes female infertility due to defective implantation. Cox2 is normally expressed in the luminal epithelium and stroma at the site of blastocyst attachment, but luminal epithelial COX2 expression is absent with loss of Klf5. This is associated with the retention of the epithelium around the implantation chamber with arrested embryonic growth. These results suggest that Klf5 is indispensable for normal implantation.