Publications by authors named "William Smoyer"

90 Publications

A pediatric gateway initiative for glomerular disease: introducing PIONEER.

Kidney Int 2021 03;99(3):515-518

Department of Pediatrics, Division of Nephrology, New York University Grossman School of Medicine, New York, New York, USA. Electronic address:

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http://dx.doi.org/10.1016/j.kint.2020.11.013DOI Listing
March 2021

Nephrotic syndrome disease activity is proportional to its associated hypercoagulopathy.

Thromb Res 2021 Feb 16;201:50-59. Epub 2021 Feb 16.

Center for Clinical and Translational Research, Abigail Wexner Research Institute at Nationwide Children's, Columbus, OH, USA; Division of Hematology/Oncology/Blood & Marrow Transplantation, Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH, USA. Electronic address:

Introduction: Nephrotic syndrome (NS) is associated with an acquired hypercoagulopathy that drives its strong predilection for life-threatening thrombosis. We previously demonstrated that hypercoagulopathy is proportional to NS disease severity in animal models. Therefore, hypercoagulopathy and disease severity may inform thrombosis risk and better guide therapeutic decision making. The objective of this study was thus to establish the relationship between disease severity and hypercoagulopathy in human NS.

Materials And Methods: Thrombin generation assays (TGA) were performed on biorepository plasma samples from a prospective longitudinal NS cohort study. TGA was also determined on a separate cohort of incident NS patients. Multivariable regression was used to build NS-hypercoagulopathy relationship models.

Results: Endogenous thrombin potential (ETP) was the TGA parameter most strongly correlated with NS severity and was proportional to conventional measures of NS disease activity including proteinuria, hypercholesterolemia, and hypoalbuminemia. The overall disease activity model was well correlated with ETP (R = 0.38). The relationship with disease activity was confirmed in the second cohort. These models further revealed that ETP is related to disease activity in a manner dependent on remission status.

Conclusion: Consistent with our previously reported animal model observations, we found that the combination of proteinuria, hypercholesterolemia, and hypoalbuminemia correlated with ETP-defined hypercoagulopathy. Hypercoagulopathy improved significantly with partial or complete NS remission. These data are expected to inform studies designed to stratify thrombotic risk for patients with NS.
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http://dx.doi.org/10.1016/j.thromres.2021.02.007DOI Listing
February 2021

SARS-CoV-2 vaccine testing and trials in the pediatric population: biologic, ethical, research, and implementation challenges.

Pediatr Res 2021 Feb 24. Epub 2021 Feb 24.

Institute for Clinical and Translational Science, UC Irvine, Irvine, CA, USA.

As the nation implements SARS-CoV-2 vaccination in adults at an unprecedented scale, it is now essential to focus on the prospect of SARS-CoV-2 vaccinations in pediatric populations. To date, no children younger than 12 years have been enrolled in clinical trials. Key challenges and knowledge gaps that must be addressed include (1) rationale for vaccines in children, (2) possible effects of immune maturation during childhood, (3) ethical concerns, (4) unique needs of children with developmental disorders and chronic conditions, (5) health inequities, and (6) vaccine hesitancy. Because COVID-19 is minimally symptomatic in the vast majority of children, a higher acceptable risk threshold is required when evaluating pediatric clinical trials. Profound differences in innate and adaptive immunity during childhood and adolescence are known to affect vaccine responsiveness for a variety of childhood diseases. COVID-19 and the accompanying social disruption, such as the school shutdowns, has been disproportionately damaging to minority and low-income children. In this commentary, we briefly address each of these key issues, specify research gaps, and suggest a broader learning health system approach to accelerate testing and clinical trial development for an ethical and effective strategy to implement a pediatric SARS-CoV-2 vaccine as rapidly and safely as possible. IMPACT: As the US begins an unprecedented implementation of SARS-CoV-2 vaccination, substantial knowledge gaps have yet to be addressed regarding vaccinations in the pediatric population. Maturational changes in the immune system during childhood have influenced the effectiveness of pediatric vaccines for other diseases and conditions, and could affect SARS-CoV-2 vaccine responsiveness in children. Given that COVID-19 disease is far milder in the majority of children than in adults, the risk-benefit of a pediatric SARS-CoV-2 vaccine must be carefully weighed. The needs of children with developmental disabilities and with chronic disease must be addressed. Minority and low-income children have been disproportionately adversely affected by the COVID-19 pandemic; care must be taken to address issues of health equity regarding pediatric SARS-CoV-2 vaccine trials and allocation. Research and strategies to address general vaccine hesitancy in communities must be addressed in the context of pediatric SARS-CoV-2 vaccines.
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http://dx.doi.org/10.1038/s41390-021-01402-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903864PMC
February 2021

Sulfatase 2 Is Associated with Steroid Resistance in Childhood Nephrotic Syndrome.

J Clin Med 2021 Feb 2;10(3). Epub 2021 Feb 2.

Center for Clinical and Translational Research, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA.

Glucocorticoid (GC) resistance complicates the treatment of ~10-20% of children with nephrotic syndrome (NS), yet the molecular basis for resistance remains unclear. We used RNAseq analysis and in silico algorithm-based approaches on peripheral blood leukocytes from 12 children both at initial NS presentation and after ~7 weeks of GC therapy to identify a 12-gene panel able to differentiate steroid resistant NS (SRNS) from steroid-sensitive NS (SSNS). Among this panel, subsequent validation and analyses of one biologically relevant candidate, sulfatase 2 (SULF2), in up to a total of 66 children, revealed that both SULF2 leukocyte expression and plasma arylsulfatase activity Post/Pre therapy ratios were greater in SSNS vs. SRNS. However, neither plasma SULF2 endosulfatase activity (measured by VEGF binding activity) nor plasma VEGF levels, distinguished SSNS from SRNS, despite VEGF's reported role as a downstream mediator of SULF2's effects in glomeruli. Experimental studies of NS-related injury in both rat glomeruli and cultured podocytes also revealed decreased SULF2 expression, which were partially reversible by GC treatment of podocytes. These findings together suggest that SULF2 levels and activity are associated with GC resistance in NS, and that SULF2 may play a protective role in NS via the modulation of downstream mediators distinct from VEGF.
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http://dx.doi.org/10.3390/jcm10030523DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867139PMC
February 2021

Results of the PROPINE randomized controlled trial: determining the ever-elusive target, the optimal plan for relapses of nephrotic syndrome in children.

Kidney Int 2021 02;99(2):311-313

Department of Pediatrics, The Ohio State University College of Medicine, Nationwide Children's Hospital, Columbus, Ohio, USA; Center for Clinical and Translational Research, Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, Ohio, USA.

Best treatments for initial presentation and relapses in children with nephrotic syndrome (NS) are still to be defined. The PROPINE study, published in this issue of Kidney International, demonstrates for relapse of childhood NS, the non-inferiority of a short taper (over 36 days) after remission with steroids. This study reinforces the need for more well-designed studies and the incorporation of predictive biomarkers, genetic studies, and other details to personalize treatment for each child with idiopathic NS.
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http://dx.doi.org/10.1016/j.kint.2020.10.034DOI Listing
February 2021

Biomarkers in pediatric glomerulonephritis and nephrotic syndrome.

Pediatr Nephrol 2021 Jan 3. Epub 2021 Jan 3.

Center for Clinical and Translational Research, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.

Glomerular diseases are often chronic or recurring and thus associated with a tremendous physical, psychological, and economic burden. Their etiologies are often unknown, and their pathogeneses are frequently poorly understood. The diagnoses and management of these diseases are therefore based on clinical features, traditional laboratory markers, and, often, kidney pathology. However, the clinical presentation can be highly variable, the kidney pathology may not establish a definitive diagnosis, and the therapeutic responses and resulting clinical outcomes are often unpredictable. To try to address these challenges, significant research efforts have been made over the last decade to identify potential biomarkers that can help clinicians optimize the diagnosis and prognosis at clinical presentation, as well as help predict long-term outcomes. Unfortunately, these efforts have to date only identified a single biomarker for glomerular disease that has been fully validated and developed for widespread clinical use (anti-PLA2R antibodies to diagnose membranous nephropathy). In this manuscript, we review the definitions and development of biomarkers, as well as the current knowledge on both historical and novel candidate biomarkers of glomerular disease, with an emphasis on those associated with idiopathic nephrotic syndrome.
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http://dx.doi.org/10.1007/s00467-020-04867-yDOI Listing
January 2021

Long-Term Outcomes of C3 Glomerulopathy and Immune-Complex Membranoproliferative Glomerulonephritis in Children.

Kidney Int Rep 2020 Dec 3;5(12):2313-2324. Epub 2020 Oct 3.

Division of Nephrology, The Hospital for Sick Children, Toronto, Ontario, Canada.

Introduction: The reclassification of membranoproliferative glomerulonephritis (MPGN) into immune-complex MPGN (IC-MPGN) and C3 glomerulopathy (C3G) has provided insights into 2 distinct diseases. Although outcomes in adults are poor in both diseases, the pediatric literature is scarce and limited to small, single-center cohorts.

Methods: We conducted a retrospective analysis of 165 pediatric patients across 17 hospitals to compare outcomes between children with IC-MPGN and C3G.

Results: Forty-two percent of patients initially diagnosed with MPGN were reclassified as C3G after a review of renal biopsy reports. There was a trend toward higher serum creatinine levels in patients with C3G compared with IC-MPGN both at diagnosis (mean 168.9 [range 45.4-292.4] vs. 93.7 [range 70.7-116.6] μmol/l,  = 0.25) and after a mean follow-up time of 4 years (mean 145.0 (range -8.1 to 298.1) vs 99.1 (range 46.3-151.9) μmol/l,  = 0.47), although the estimated glomerular filtration rate (eGFR) was not significantly different. Steroid treatment was associated with a significant improvement in eGFR versus no steroids in C3G (mean +43.0 (range 12.9-73.0) vs. -3.0 (range -23.1 to 17.2) ml/min per 1.73 m,  = 0.02) but not in IC-MPGN. Overall kidney function was preserved in both groups although hypertension remained prevalent in 42.5% of the cohort at the last follow-up, and the urine protein/creatinine ratio remained elevated (mean 253.8 [range 91.9-415.7] mg/mmol).

Conclusion: This large pediatric IC-MPGN/C3G cohort revealed nearly half of the patients were misclassified, and there may be a trend toward worse renal prognosis in C3G although they may have greater steroid responsiveness. The overall prognosis appears to be more favorable than in adults; however, persistent hypertension and proteinuria suggest suboptimal disease control.
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http://dx.doi.org/10.1016/j.ekir.2020.09.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710848PMC
December 2020

Challenges of access to kidney care for children in low-resource settings.

Nat Rev Nephrol 2021 01 1;17(1):33-45. Epub 2020 Oct 1.

Nationwide Children's Hospital, Columbus, OH, USA.

Kidney disease is a global public health concern across the age spectrum, including in children. However, our understanding of the true burden of kidney disease in low-resource areas is often hampered by a lack of disease awareness and access to diagnosis. Chronic kidney disease (CKD) in low-resource settings poses multiple challenges, including late diagnosis, the need for ongoing access to care and the frequent unavailability of costly therapies such as dialysis and transplantation. Moreover, children in such settings are at particular risk of acute kidney injury (AKI) owing to preventable and/or reversible causes - many children likely die from potentially reversible kidney disease because they lack access to appropriate care. Acute peritoneal dialysis (PD) is an important low-cost treatment option. Initiatives, such as the Saving Young Lives programme, to train local medical staff from low-resource areas to provide care for AKI, including acute PD, have already saved hundreds of children. Future priorities include capacity building for both educational purposes and to provide further resources for AKI management. As local knowledge and confidence increase, CKD management strategies should also develop. Increased awareness and advocacy at both the local government and international levels will be required to continue to improve the diagnosis and treatment of AKI and CKD in children worldwide.
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http://dx.doi.org/10.1038/s41581-020-00338-7DOI Listing
January 2021

Nephrotic syndrome-associated hypercoagulopathy is alleviated by both pioglitazone and glucocorticoid which target two different nuclear receptors.

Physiol Rep 2020 08;8(15):e14515

Center for Clinical & Translational Research, The Abigail Wexner Research Institute at Nationwide Children's, Columbus, OH, USA.

Background: Thrombosis is a potentially life-threatening nephrotic syndrome (NS) complication. We have previously demonstrated that hypercoagulopathy is proportional to NS severity in rat models and that pioglitazone (Pio) reduces proteinuria both independently and in combination with methylprednisolone (MP), a glucocorticoid (GC). However, the effect of these treatments on NS-associated hypercoagulopathy remains unknown. We thus sought to determine the ability of Pio and GC to alleviate NS-associated hypercoagulopathy.

Methods: Puromycin aminonucleoside-induced rat NS was treated with sham, Low- or High-dose MP, Pio, or combination (Pio + Low-MP) and plasma was collected at day 11. Plasma samples were collected from children with steroid-sensitive NS (SSNS) and steroid-resistant NS (SRNS) upon presentation and after 7 weeks of GC therapy. Plasma endogenous thrombin potential (ETP), antithrombin (AT) activity, and albumin (Alb) were measured using thrombin generation, amidolytic, and colorimetric assays, respectively.

Results: In a rat model of NS, both High-MP and Pio improved proteinuria and corrected hypoalbuminemia, ETP and AT activity (p < .05). Proteinuria (p = .005) and hypoalbuminemia (p < .001) were correlated with ETP. In childhood NS, while ETP was not different at presentation, GC therapy improved proteinuria, hypoalbuminemia, and ETP in children with SSNS (p < .001) but not SRNS (p = .330).

Conclusions: Both Pio and GC diminish proteinuria and significantly alleviate hypercoagulopathy. Both Pio and MP improved hypercoagulopathy in rats, and successful GC therapy (SSNS) also improved hypercoagulopathy in childhood NS. These data suggest that even a partial reduction in proteinuria may reduce NS-associated thrombotic risk.
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http://dx.doi.org/10.14814/phy2.14515DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7415912PMC
August 2020

Renal Survival in Children with Glomerulonephritis with Crescents: A Pediatric Nephrology Research Consortium Cohort Study.

J Clin Med 2020 Jul 26;9(8). Epub 2020 Jul 26.

Pediatric Nephrology, Baylor College of Medicine and Texas Children's Hospital, Houston, TX 77030, USA.

There is no evidence-based definition for diagnosing crescentic glomerulonephritis. The prognostic implications of crescentic lesions on kidney biopsy have not been quantified. Our objective was to determine risk factors for end-stage kidney disease (ESKD) in patients with glomerulonephritis and crescents on kidney biopsy. A query of the Pediatric Nephrology Research Consortium's Pediatric Glomerulonephritis with Crescents registry identified 305 patients from 15 centers. A retrospective cohort study was performed with ESKD as the primary outcome. Median age at biopsy was 11 years (range 1-21). The percentage of crescents was 3-100% (median 20%). Etiologies included IgA nephropathy (23%), lupus (21%), IgA vasculitis (19%) and ANCA-associated GN (13%), post-infectious GN (5%), and anti-glomerular basement membrane disease (3%). The prevalence of ESKD was 12% at one year and 16% at last follow-up (median = 3 years, range 1-11). Median time to ESKD was 100 days. Risk factors for ESKD included %crescents, presence of fibrous crescents, estimated GFR, and hypertension at biopsy. For each 1% increase in %crescents, there was a 3% decrease in log odds of 1-year renal survival ( = 0.003) and a 2% decrease in log odds of renal survival at last follow-up ( < 0.001). These findings provide an evidence base for enrollment criteria for crescentic glomerulonephritis in future clinical trials.
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http://dx.doi.org/10.3390/jcm9082385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464981PMC
July 2020

Saving more young lives in Africa.

Perit Dial Int 2020 09 18;40(5):438-440. Epub 2020 Jun 18.

The Research Institute at 2650Nationwide Childrens Hospital, Centre for Clinical and Translational Research, Columbus, OH, USA.

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http://dx.doi.org/10.1177/0896860820931662DOI Listing
September 2020

Long-term ACE inhibition in Alport syndrome: are the benefits worth the risks?

Kidney Int 2020 06;97(6):1104-1106

Department of Pediatrics, Nationwide Children's Hospital, Columbus, Ohio, USA.

Gross et al. present results of the EARLY PRO-TECT trial, a randomized controlled trial of ramipril versus placebo in children with early-stage Alport syndrome. Although under-enrolled and not a positive trial in the traditional sense, EARLY PRO-TECT does provide strong supportive evidence for both long-term safety and a clinical benefit of early treatment with angiotensin-converting enzyme inhibitors in slowing the progression of both albuminuria and estimated glomerular filtration rate decline in children with Alport syndrome.
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http://dx.doi.org/10.1016/j.kint.2020.01.030DOI Listing
June 2020

IPNA clinical practice recommendations for the diagnosis and management of children with steroid-resistant nephrotic syndrome.

Pediatr Nephrol 2020 08 7;35(8):1529-1561. Epub 2020 May 7.

Department of Paediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School Children's Hospital, Hannover, Germany.

Idiopathic nephrotic syndrome newly affects 1-3 per 100,000 children per year. Approximately 85% of cases show complete remission of proteinuria following glucocorticoid treatment. Patients who do not achieve complete remission within 4-6 weeks of glucocorticoid treatment have steroid-resistant nephrotic syndrome (SRNS). In 10-30% of steroid-resistant patients, mutations in podocyte-associated genes can be detected, whereas an undefined circulating factor of immune origin is assumed in the remaining ones. Diagnosis and management of SRNS is a great challenge due to its heterogeneous etiology, frequent lack of remission by further immunosuppressive treatment, and severe complications including the development of end-stage kidney disease and recurrence after renal transplantation. A team of experts including pediatric nephrologists and renal geneticists from the International Pediatric Nephrology Association (IPNA), a renal pathologist, and an adult nephrologist have now developed comprehensive clinical practice recommendations on the diagnosis and management of SRNS in children. The team performed a systematic literature review on 9 clinically relevant PICO (Patient or Population covered, Intervention, Comparator, Outcome) questions, formulated recommendations and formally graded them at a consensus meeting, with input from patient representatives and a dietician acting as external advisors and a voting panel of pediatric nephrologists. Research recommendations are also given.
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http://dx.doi.org/10.1007/s00467-020-04519-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7316686PMC
August 2020

Predicting and Defining Steroid Resistance in Pediatric Nephrotic Syndrome Using Plasma Metabolomics.

Kidney Int Rep 2020 Jan 19;5(1):81-93. Epub 2019 Sep 19.

National Institutes of Health Eastern Regional Comprehensive Metabolomics Resource Core (ERCMRC) at University of North Carolina, Chapel Hill, North Carolina, USA.

Introduction: Nephrotic syndrome (NS) is a kidney disease that affects both children and adults. Glucocorticoids have been the primary therapy for >60 years but are ineffective in approximately 20% of children and approximately 50% of adult patients. Unfortunately, patients with steroid-resistant NS (SRNS; vs. steroid-sensitive NS [SSNS]) are at high risk for both glucocorticoid-induced side effects and disease progression.

Methods: We performed proton nuclear magnetic resonance (H NMR) metabolomic analyses on plasma samples ( = 86) from 45 patients with NS (30 SSNS and 15 SRNS) obtained at initial disease presentation before glucocorticoid initiation and after approximately 7 weeks of glucocorticoid therapy to identify candidate biomarkers able to either predict SRNS before treatment or define critical molecular pathways/targets regulating steroid resistance.

Results: Stepwise logistic regression models identified creatinine concentration and glutamine concentration (odds ratio [OR]: 1.01; 95% confidence interval [CI]: 0.99-1.02) as 2 candidate biomarkers predictive of SRNS, and malonate concentration (OR: 0.94; 95% CI: 0.89-1.00) as a third candidate predictive biomarker using a similar model (only in children >3 years). In addition, paired-sample analyses identified several candidate biomarkers with the potential to identify mechanistic molecular pathways/targets that regulate clinical steroid resistance, including lipoproteins, adipate, pyruvate, creatine, glucose, tyrosine, valine, glutamine, and sn-glycero-3-phosphcholine.

Conclusion: Metabolomic analyses of serial plasma samples from children with SSNS and SRNS identified elevated creatinine and glutamine concentrations, and reduced malonate concentrations, as auspicious candidate biomarkers to predict SRNS at disease onset in pediatric NS, as well as additional candidate biomarkers with the potential to identify mechanistic molecular pathways that may regulate clinical steroid resistance.
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http://dx.doi.org/10.1016/j.ekir.2019.09.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6943762PMC
January 2020

Predicting and Defining Steroid Resistance in Pediatric Nephrotic Syndrome Using Plasma Proteomics.

Kidney Int Rep 2020 Jan 19;5(1):66-80. Epub 2019 Sep 19.

The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.

Introduction: Nephrotic syndrome (NS) is a characterized by massive proteinuria, edema, hypoalbuminemia, and dyslipidemia. Glucocorticoids (GCs), the primary therapy for >60 years, are ineffective in approximately 50% of adults and approximately 20% of children. Unfortunately, there are no validated biomarkers able to predict steroid-resistant NS (SRNS) or to define the pathways regulating SRNS.

Methods: We performed proteomic analyses on paired pediatric NS patient plasma samples obtained both at disease presentation before glucocorticoid initiation and after approximately 7 weeks of GC therapy to identify candidate biomarkers able to either predict steroid resistance before treatment or define critical molecular pathways/targets regulating steroid resistance.

Results: Proteomic analyses of 15 paired NS patient samples identified 215 prevalent proteins, including 13 candidate biomarkers that predicted SRNS before GC treatment, and 66 candidate biomarkers that mechanistically differentiated steroid-sensitive NS (SSNS) from SRNS. Ingenuity Pathway Analyses and protein networking pathways approaches further identified proteins and pathways associated with SRNS. Validation using 37 NS patient samples (24 SSNS/13 SRNS) confirmed vitamin D binding protein (VDB) and APOL1 as strong predictive candidate biomarkers for SRNS, and VDB, hemopexin (HPX), adiponectin (ADIPOQ), sex hormone-binding globulin (SHBG), and APOL1 as strong candidate biomarkers to mechanistically distinguish SRNS from SSNS. Logistic regression analysis identified a candidate biomarker panel (VDB, ADIPOQ, and matrix metalloproteinase 2 [MMP-2]) with significant ability to predict SRNS at disease presentation ( = 0.003; area under the receiver operating characteristic curve = 0.78).

Conclusion: Plasma proteomic analyses and immunoblotting of serial samples in childhood NS identified a candidate biomarker panel able to predict SRNS at disease presentation, as well as candidate molecular targets/pathways associated with clinical steroid resistance.
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http://dx.doi.org/10.1016/j.ekir.2019.09.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6943770PMC
January 2020

Using Electronic Health Record Data to Rapidly Identify Children with Glomerular Disease for Clinical Research.

J Am Soc Nephrol 2019 12 15;30(12):2427-2435. Epub 2019 Nov 15.

Division of Nephrology.

Background: The rarity of pediatric glomerular disease makes it difficult to identify sufficient numbers of participants for clinical trials. This leaves limited data to guide improvements in care for these patients.

Methods: The authors developed and tested an electronic health record (EHR) algorithm to identify children with glomerular disease. We used EHR data from 231 patients with glomerular disorders at a single center to develop a computerized algorithm comprising diagnosis, kidney biopsy, and transplant procedure codes. The algorithm was tested using PEDSnet, a national network of eight children's hospitals with data on >6.5 million children. Patients with three or more nephrologist encounters (=55,560) not meeting the computable phenotype definition of glomerular disease were defined as nonglomerular cases. A reviewer blinded to case status used a standardized form to review random samples of cases (=800) and nonglomerular cases (=798).

Results: The final algorithm consisted of two or more diagnosis codes from a qualifying list or one diagnosis code and a pretransplant biopsy. Performance characteristics among the population with three or more nephrology encounters were sensitivity, 96% (95% CI, 94% to 97%); specificity, 93% (95% CI, 91% to 94%); positive predictive value (PPV), 89% (95% CI, 86% to 91%); negative predictive value, 97% (95% CI, 96% to 98%); and area under the receiver operating characteristics curve, 94% (95% CI, 93% to 95%). Requiring that the sum of nephrotic syndrome diagnosis codes exceed that of glomerulonephritis codes identified children with nephrotic syndrome or biopsy-based minimal change nephropathy, FSGS, or membranous nephropathy, with 94% sensitivity and 92% PPV. The algorithm identified 6657 children with glomerular disease across PEDSnet, ≥50% of whom were seen within 18 months.

Conclusions: The authors developed an EHR-based algorithm and demonstrated that it had excellent classification accuracy across PEDSnet. This tool may enable faster identification of cohorts of pediatric patients with glomerular disease for observational or prospective studies.
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http://dx.doi.org/10.1681/ASN.2019040365DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6900784PMC
December 2019

Dyslipidemia and cardiovascular health in childhood nephrotic syndrome.

Pediatr Nephrol 2020 09 13;35(9):1601-1619. Epub 2019 Jul 13.

Department of Pediatrics, College of Medicine, The Ohio State University, Columbus, OH, USA.

Children with steroid-resistant nephrotic syndrome (SRNS) are exposed to multiple cardiovascular risk factors predisposing them to accelerated atherosclerosis. This risk is negligible in steroid-sensitive nephrotic syndrome, but a substantial proportion of children with SRNS progress to chronic kidney disease, exacerbating the already existing cardiovascular risk. While dyslipidemia is an established modifiable risk factor for cardiovascular disease in adults with NS, it is uncertain to what extent analogous risks exist for children. There is increasing evidence of accelerated atherosclerosis in children with persistently high lipid levels, especially in refractory NS. Abnormalities of lipid metabolism in NS include hypertriglyceridemia and hypercholesterolemia due to elevated apolipoprotein B-containing lipoproteins, decreased lipoprotein lipase and hepatic lipase activity, increased hepatic PCSK9 levels, and reduced hepatic uptake of high-density lipoprotein. Existing guidelines for the management of dyslipidemia in children may be adapted to target lower lipid levels in children with NS, but they will most likely require both lifestyle modifications and pharmacological therapy. While there is a lack of data from randomized controlled trials in children with NS demonstrating the benefit of lipid-lowering drugs, therapies including statins, bile acid sequestrants, fibrates, ezetimibe, and LDL apheresis have all been suggested and/or utilized. However, concerns with the use of lipid-lowering drugs in children include unclear side effect profiles and unknown long-term impacts on neurological development and puberty. The recent introduction of anti-PCSK9 monoclonal antibodies and other therapies targeted to the molecular mechanisms of lipid transport disrupted in NS holds promise for the future treatment of dyslipidemia in NS.
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http://dx.doi.org/10.1007/s00467-019-04301-yDOI Listing
September 2020

Rituximab Use in the Management of Childhood Nephrotic Syndrome.

Front Pediatr 2019 10;7:178. Epub 2019 May 10.

Division of Nephrology, Nationwide Children's Hospital, The Ohio State University College of Medicine, Columbus, OH, United States.

Childhood nephrotic syndrome is a challenging and often persistent renal disorder, and its incidence varies between different ethnicities and regions. Corticosteroids have been the main treatment for decades and are effective in most children with idiopathic NS, although 10-15% of these children become steroid resistant. Furthermore, some initially steroid sensitive children follow a steroid dependent or frequently relapsing course and are therefore at increased risk for developing steroid toxicity. In such children, alternative immunosuppressive medications are used to induce and/or maintain remission of NS. One such drug, rituximab, is a monoclonal antibody directed against the B lymphocyte CD20 marker which induces depletion of B cells, and has shown promising results in the management of NS in children. In this review, we summarize recent studies on the efficacy and safety of rituximab in the different types of childhood nephrotic syndrome, the known and potential mechanisms of action of rituximab, its possible complications and side effects, and the available and potential biomarkers of rituximab activity.
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http://dx.doi.org/10.3389/fped.2019.00178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6524616PMC
May 2019

Health-related quality of life in glomerular disease.

Kidney Int 2019 05 27;95(5):1209-1224. Epub 2019 Feb 27.

Department of Medicine, University of Michigan, Ann Arbor, Michigan, USA.

There is scant literature describing the effect of glomerular disease on health-related quality of life (HRQOL). The Cure Glomerulonephropathy study (CureGN) is an international longitudinal cohort study of children and adults with four primary glomerular diseases (minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, and IgA nephropathy). HRQOL is systematically assessed using items from the Patient-Reported Outcomes Measurement Informative System (PROMIS). We assessed the relationship between HRQOL and demographic and clinical variables in 478 children and 1115 adults at the time of enrollment into CureGN. Domains measured by PROMIS items included global assessments of health, mobility, anxiety, fatigue, and sleep impairment, as well as a derived composite measure incorporating all measured domains. Multivariable models were created that explained 7 to 32% of variance in HRQOL. Patient-reported edema consistently had the strongest and most robust association with each measured domain of HRQOL in multivariable analysis (adjusted β [95% CI] for composite PROMIS score in children, -5.2 [-7.1 to -3.4]; for composite PROMIS score in adults, -6.1 [-7.4 to -4.9]). Female sex, weight (particularly obesity), and estimated glomerular filtration rate were also associated with some, but not all, domains of HRQOL. Primary diagnosis, disease duration, and exposure to immunosuppression were not associated with HRQOL after adjustment. Sensitivity analyses and interaction testing demonstrated no significant association between disease duration or immunosuppression and any measured domain of HRQOL. Thus, patient-reported edema has a consistent negative association with HRQOL in patients with primary glomerular diseases, with substantially greater impact than other demographic and clinical variables.
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http://dx.doi.org/10.1016/j.kint.2018.12.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6743723PMC
May 2019

"Learn From Every Patient": How a Learning Health System Can Improve Patient Care.

Pediatr Qual Saf 2018 Sep-Oct;3(5):e100. Epub 2018 Sep 5.

Department of Pediatrics, Nationwide Children's Hospital, Columbus, Dayton, Ohio.

Aim: We created a Learning Health System, the "Learn From Every Patient" program, embedded in our cerebral palsy team clinic. This program was designed to simultaneously provide clinical care while systematically collecting data for quality improvement and research projects on all patients.

Method: Clinicians created tools within the Electronic Health Record to discretely capture data for clinical use which was also available for quality improvement/research efforts. At baseline, all patients in our clinic received annual hip x-rays to screen for hip displacement. Using our "Learn From Every Patient" database, we reviewed the outcomes for the most mildly affected patients, Level I on the Gross Motor Functional Classification System.

Results: One hundred thirty-two patients were classified as Gross Motor Functional Classification System Level I. During the study period, these patients received 212 pelvis x-rays, viewing 424 hips, of which 419 (98.8%) were normal. Five hips (1.2%) had < 30% displacement. None had any hip-related symptoms nor required any procedures during the period. We used these data to create an evidence-based change in our standardized hip screening procedure by eliminating annual screening x-rays for this population.

Interpretation: This implementation of a local learning health system approach to systematically collect research data simultaneously with routine clinical care enabled us to implement an evidence-based improvement in clinical practice. This complete integration of research into clinical care improved care by reducing radiation exposure, while simultaneously reducing health care costs.
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http://dx.doi.org/10.1097/pq9.0000000000000100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6221586PMC
September 2018

Clinical Characteristics and Treatment Patterns of Children and Adults With IgA Nephropathy or IgA Vasculitis: Findings From the CureGN Study.

Kidney Int Rep 2018 Nov 3;3(6):1373-1384. Epub 2018 Aug 3.

Department of Medicine, Division of Nephrology, Columbia University College of Physicians and Surgeons, New York, New York, USA.

Introduction: The Cure Glomerulonephropathy Network (CureGN) is a 66-center longitudinal observational study of patients with biopsy-confirmed minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, or IgA nephropathy (IgAN), including IgA vasculitis (IgAV). This study describes the clinical characteristics and treatment patterns in the IgA cohort, including comparisons between IgAN versus IgAV and adult versus pediatric patients.

Methods: Patients with a diagnostic kidney biopsy within 5 years of screening were eligible to join CureGN. This is a descriptive analysis of clinical and treatment data collected at the time of enrollment.

Results: A total of 667 patients (506 IgAN, 161 IgAV) constitute the IgAN/IgAV cohort (382 adults, 285 children). At biopsy, those with IgAV were younger (13.0 years vs. 29.6 years,  < 0.001), more frequently white (89.7% vs. 78.9%,  = 0.003), had a higher estimated glomerular filtration rate (103.5 vs. 70.6 ml/min per 1.73 m,  < 0.001), and lower serum albumin (3.4 vs. 3.8 g/dl,  < 0.001) than those with IgAN. Adult and pediatric individuals with IgAV were more likely than those with IgAN to have been treated with immunosuppressive therapy at or prior to enrollment (79.5% vs. 54.0%,  < 0.001).

Conclusion: This report highlights clinical differences between IgAV and IgAN and between children and adults with these diagnoses. We identified differences in treatment with immunosuppressive therapies by disease type. This description of baseline characteristics will serve as a foundation for future CureGN studies.
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http://dx.doi.org/10.1016/j.ekir.2018.07.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6224619PMC
November 2018

CureGN Study Rationale, Design, and Methods: Establishing a Large Prospective Observational Study of Glomerular Disease.

Am J Kidney Dis 2019 02 9;73(2):218-229. Epub 2018 Nov 9.

Center for Translational Science, Children's National Health System, Washington, DC.

Rationale & Objectives: Glomerular diseases, including minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, and immunoglobulin A (IgA) nephropathy, share clinical presentations, yet result from multiple biological mechanisms. Challenges to identifying underlying mechanisms, biomarkers, and new therapies include the rarity of each diagnosis and slow progression, often requiring decades to measure the effectiveness of interventions to prevent end-stage kidney disease (ESKD) or death.

Study Design: Multicenter prospective cohort study.

Setting & Participants: Cure Glomerulonephropathy (CureGN) will enroll 2,400 children and adults with minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, or IgA nephropathy (including IgA vasculitis) and a first diagnostic kidney biopsy within 5 years. Patients with ESKD and those with secondary causes of glomerular disease are excluded.

Exposures: Clinical data, including medical history, medications, family history, and patient-reported outcomes, are obtained, along with a digital archive of kidney biopsy images and blood and urine specimens at study visits aligned with clinical care 1 to 4 times per year.

Outcomes: Patients are followed up for changes in estimated glomerular filtration rate, disease activity, ESKD, and death and for nonrenal complications of disease and treatment, including infection, malignancy, cardiovascular, and thromboembolic events.

Analytical Approach: The study design supports multiple longitudinal analyses leveraging the diverse data domains of CureGN and its ancillary program. At 2,400 patients and an average of 2 years' initial follow-up, CureGN has 80% power to detect an HR of 1.4 to 1.9 for proteinuria remission and a mean difference of 2.1 to 3.0mL/min/1.73m in estimated glomerular filtration rate per year.

Limitations: Current follow-up can only detect large differences in ESKD and death outcomes.

Conclusions: Study infrastructure will support a broad range of scientific approaches to identify mechanistically distinct subgroups, identify accurate biomarkers of disease activity and progression, delineate disease-specific treatment targets, and inform future therapeutic trials. CureGN is expected to be among the largest prospective studies of children and adults with glomerular disease, with a broad goal to lessen disease burden and improve outcomes.
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http://dx.doi.org/10.1053/j.ajkd.2018.07.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6348011PMC
February 2019

Association of infections and venous thromboembolism in hospitalized children with nephrotic syndrome.

Pediatr Nephrol 2019 02 7;34(2):261-267. Epub 2018 Sep 7.

University of Minnesota Masonic Children's Hospital, Minneapolis, MN, USA.

Background: Nephrotic syndrome (NS) results in hypercoagulability and increased risk of infection. Furthermore, infection increases the risk of venous thromboembolism (VTE). Our objective was to determine the prevalence of infection, VTE, and the associated outcomes among a cohort of hospitalized children with NS.

Methods: All children with NS admitted to 17 pediatric hospitals across North America from 2010 to 2012 were included. Prevalence of infection and VTE was determined. Wilcoxon rank-sum and logistic regression were performed.

Results: Seven-hundred thirty hospitalizations occurred among 370 children with NS. One-hundred forty-eight children (40%) had ≥ 1 infection (211 episodes) and 11 (3%) had VTE. Those with VTE had infection more frequently (p = 0.046) and were younger at NS diagnosis (3.0 vs. 4.0 years; p = 0.008). The most common infectious pathogen identified was Streptococcus pneumoniae. The median hospital length of stay for those with infection [10 vs 5 days (p < 0.0001)] or VTE [22 vs 6 days (p < 0.0001)] was longer than those without either complication. Of those with infection, 13% had an intensive care unit (ICU) stay compared with 3.3% of those without infection. Median ICU stay was 4 days in those with VTE compared to 0 days in those without (p < 0.001). By logistic regression, only the number of ICU days was associated with VTE (OR 1.074, 95% CI 1.013-1.138).

Conclusions: Hospitalized children with NS have high rates of infection. Presence of VTE was associated with infection. Both were associated with longer hospitalizations and ICU stays.
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http://dx.doi.org/10.1007/s00467-018-4072-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6628263PMC
February 2019

Intravenous Ribavirin for Parainfluenza and Respiratory Syncytial Virus in an Infant Receiving Extracorporeal Membrane Oxygenation and Continuous Renal Replacement Therapy.

J Pediatr Pharmacol Ther 2018 Jul-Aug;23(4):337-342

Background: Viral bronchiolitis remains a significant cause of hospitalization as well as morbidity and mortality during the first year of life, with treatment options beyond supportive care being limited. In cases of severe illness, ribavirin may offer therapeutic benefit.

Objective: We report the use of intravenous (IV) ribavirin in an infant requiring concomitant venovenous extracorporeal membrane oxygenation (VV-ECMO) and continuous venovenous hemofiltration (CVVH) for respiratory syncytial virus (RSV) and parainfluenza virus (PIV) coinfection.

Patients And Methods: A 5-week-old male former 33-week preterm infant was admitted with respiratory failure and subsequently tested positive for RSV and PIV-type 1 infection. Progressive clinical deterioration subsequently required the initiation of both VV-ECMO and CVVH. Although the patient received combined VV-ECMO and CVVH, IV ribavirin was administered, and serial plasma and ultrafiltrate samples were obtained for pharmacokinetic analyses after the first dose (collection period 1) and again after an estimated 5 half-lives (collection period 2).

Results: Pharmacokinetics for collection period 1 demonstrated a calculated C of 11.99 mg/L, an AUC of 43.32 mg·hr/L, k 0.26 hr, t½ 2.69 hr, Vd 10.04 L (2.92 L/kg, using patient's dosing weight 3.43 kg), CL 43.47 mL/min, and CL 6.75 mL/min. Pharmacokinetics for collection period 2 demonstrated a calculated C of 10.31 mg/L, AUC of 52.55 mg· hr/L, k 0.06 hr, t½ 10.69 hr, Vd 17.5 L (5.1 L/kg), and CL 17.44 mL/min. The sieving coefficient during collection period 1 was 1.17 (range, 1.07-1.37). The percent decline between prefilter and postfilter oxygenator was 19.1%.

Conclusion: Our patient demonstrated therapeutic concentrations of ribavirin, despite drug removal via CVVH and the ECMO oxygenator. Standard ribavirin dosing used and resultant concentrations achieved were associated with viral clearance and clinical improvement.
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http://dx.doi.org/10.5863/1551-6776-23.4.337DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6117812PMC
September 2018

Dyslipidaemia in nephrotic syndrome: mechanisms and treatment.

Nat Rev Nephrol 2017 Dec;14(1):70

This corrects the article DOI: 10.1038/nrneph.2017.155.
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http://dx.doi.org/10.1038/nrneph.2017.175DOI Listing
December 2017

Pharmacological and genetic inhibition of downstream targets of p38 MAPK in experimental nephrotic syndrome.

Am J Physiol Renal Physiol 2018 04 29;314(4):F602-F613. Epub 2017 Nov 29.

Center for Clinical and Translational Research, The Research Institute at Nationwide Children's Hospital , Columbus, Ohio.

Nie X, Chanley MA, Pengal R, Thomas DB, Agrawal S, Smoyer WE. Pharmacological and genetic inhibition of downstream targets of p38 MAPK in experimental nephrotic syndrome. Am J Physiol Renal Physiol 314: F602-F613, 2018. First published November 29, 2017; doi: 10.1152/ajprenal.00207.2017 .-The p38 MAPK pathway plays a crucial role in various glomerulopathies, with activation being associated with disease and inhibition being associated with disease amelioration. We hypothesized that the downstream targets of p38 MAPK, MAPK-activated protein kinase 2 and/or 3 (MK2 and/or MK3), play an important role in mediating injury in experimental nephrotic syndrome via their actions on their downstream substrates heat shock protein B1 (HSPB1) and cyclooxygenase-2 (COX-2). To test this hypothesis, the effects of both pharmacological and genetic inhibition of MK2 and MK3 were examined in mouse adriamycin (ADR) and rat puromycin aminonucleoside (PAN) nephropathy models. MK2, MK3, and MK2MK3 mice were generated in the Sv129 background and subjected to ADR-induced nephropathy. MK2 and MK3 protein expression was completely abrogated in the respective knockout genotypes, and massive proteinuria and renal histopathological changes developed after ADR treatment. Furthermore, renal cortical HSPB1 was induced in all four genotypes by day 21, but HSPB1 was activated only in the wild-type and MK3 mice. Expression of the stress proteins HSPB8 and glucose-regulated protein 78 (GRP78) remained unaltered across all genotypes. Finally, while MK2 and/or MK3-knockout downregulated the proinflammatory enzyme COX-2, ADR significantly induced renal cortical COX-2 only in MK2 mice. Additionally, pharmacological MK2 inhibition with PF-318 during PAN-induced nephropathy did not result in significant proteinuria reduction in rats. Together, these data suggest that while the inhibition of MK2 and/or MK3 regulates the renal stress response, our currently available approaches are not yet able to safely and effectively reduce proteinuria in experimental nephrotic syndrome and that other p38MAPK downstream targets should also be considered to improve the future treatment of glomerular disease.
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http://dx.doi.org/10.1152/ajprenal.00207.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5966757PMC
April 2018

Dyslipidaemia in nephrotic syndrome: mechanisms and treatment.

Nat Rev Nephrol 2018 Jan 27;14(1):57-70. Epub 2017 Nov 27.

Center for Clinical and Translational Research, The Research Institute at Nationwide Children's Hospital, and Department of Pediatrics, The Ohio State University, 700 Children's Drive, W303, Columbus, Ohio 43205, USA.

Nephrotic syndrome is a highly prevalent disease that is associated with high morbidity despite notable advances in its treatment. Many of the complications of nephrotic syndrome, including the increased risk of atherosclerosis and thromboembolism, can be linked to dysregulated lipid metabolism and dyslipidaemia. These abnormalities include elevated plasma levels of cholesterol, triglycerides and the apolipoprotein B-containing lipoproteins VLDL and IDL; decreased lipoprotein lipase activity in the endothelium, muscle and adipose tissues; decreased hepatic lipase activity; and increased levels of the enzyme PCSK9. In addition, there is an increase in the plasma levels of immature HDL particles and reduced cholesterol efflux. Studies from the past few years have markedly improved our understanding of the molecular pathogenesis of nephrotic syndrome-associated dyslipidaemia, and also heightened our awareness of the associated exacerbated risks of cardiovascular complications, progressive kidney disease and thromboembolism. Despite the absence of clear guidelines regarding treatment, various strategies are being increasingly utilized, including statins, bile acid sequestrants, fibrates, nicotinic acid and ezetimibe, as well as lipid apheresis, which seem to also induce partial or complete clinical remission of nephrotic syndrome in a substantial percentage of patients. Future potential treatments will likely also include inhibition of PCSK9 using recently-developed anti-PCSK9 monoclonal antibodies and small inhibitory RNAs, as well as targeting newly identified molecular regulators of lipid metabolism that are dysregulated in nephrotic syndrome.
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http://dx.doi.org/10.1038/nrneph.2017.155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5770189PMC
January 2018

Association of Serum Soluble Urokinase Receptor Levels With Progression of Kidney Disease in Children.

JAMA Pediatr 2017 11 6;171(11):e172914. Epub 2017 Nov 6.

Department of Medicine, Rush University Medical Center, Chicago, Illinois.

Importance: Conventional methods to diagnose and monitor chronic kidney disease (CKD) in children, such as creatinine level and cystatin C-derived estimated glomerular filtration rate (eGFR) and assessment of proteinuria in spot or timed urine samples, are of limited value in identifying patients at risk of progressive kidney function loss. Serum soluble urokinase receptor (suPAR) levels strongly predict incident CKD stage 3 in adults.

Objective: To determine whether elevated suPAR levels are associated with renal disease progression in children with CKD.

Design, Setting, And Participants: Post hoc analysis of 2 prospectively followed up pediatric CKD cohorts, ie, the ESCAPE Trial (1999-2007) and the 4C Study (2010-2016), with serum suPAR level measured at enrollment and longitudinal eGFR measured prospectively. In the 2 trials, a total of 898 children were observed at 30 (ESCAPE Trial; n = 256) and 55 (4C Study; n = 642) tertiary care hospitals in 13 European countries. Renal diagnoses included congenital anomalies of the kidneys and urinary tract (n = 637 [70.9%]), tubulointerstitial nephropathies (n = 92 [10.2%]), glomerulopathies (n = 69 [7.7%]), postischemic CKD (n = 42 [4.7%]), and other CKD (n = 58 [6.5%]). Total follow-up duration was up to 7.9 years, and median follow-up was 3.1 years. Analyses were conducted from October 2016 to December 2016.

Exposures: Serum suPAR level was measured at enrollment, and eGFR was measured every 2 months in the ESCAPE Trial and every 6 months in the 4C Study. The primary end point of CKD progression was a composite of 50% eGFR loss, eGFR less than 10 mL/min/1.73 m2, or initiation of renal replacement therapy.

Main Outcomes And Measures: The primary end point in this study was renal survival, defined as a composite of 50% loss of GFR that persisted for at least 1 month, the start of renal replacement therapy, or an eGFR less than 10 mL/min/1.73 m2.

Results: Of the 898 included children, 560 (62.4%) were male, and the mean (SD) patient age at enrollment was 11.9 (3.5) years. The mean (SD) eGFR was 34 (16) mL/min/1.73 m2. The 5-year end point-free renal survival was 64.5% (95% CI, 57.4-71.7) in children with suPAR levels in the lowest quartile compared with 35.9% (95% CI, 28.7-43.0) in those in the highest quartile (P < .001). By multivariable analysis, the risk of attaining the end point was higher in children with glomerulopathies and increased with age, blood pressure, proteinuria, and lower eGFR at baseline. In patients with baseline eGFR greater than 40 mL/min/1.73 m2, higher log-transformed suPAR levels were associated with a higher risk of CKD progression after adjustment for traditional risk factors (hazard ratio, 5.12; 95% CI, 1.56-16.7; P = .007).

Conclusions And Relevance: Patients with high suPAR levels were more likely to have progression of their kidney disease. Further studies should determine whether suPAR levels can identify children at risk for future CKD.
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http://dx.doi.org/10.1001/jamapediatrics.2017.2914DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6121753PMC
November 2017

Enhancing clinical trial development for pediatric kidney diseases.

Pediatr Res 2017 Nov 30;82(5):727-732. Epub 2017 Aug 30.

Center for Clinical and Translational Research, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio.

The conduct of clinical trials in small pediatric subspecialties such as pediatric nephrology is hampered by both clinical demands on the pediatric nephrologist and the small number of appropriate patients available for such studies. The American Society of Pediatric Nephrology Therapeutics Development Committee (TDC) was established to (1) identify the various stakeholders with interests and/or expertise related to clinical trials in children with kidney disease and (2) develop more effective partnerships among all parties regarding strategies for successful clinical trial development and execution. This article discusses the rationale, structure, and function of the TDC, the status of progress toward its goals, and the insights gained to date that may be useful for other subspecialties that face similar challenges.
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http://dx.doi.org/10.1038/pr.2017.180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5675130PMC
November 2017