Digital Pathology Evaluation in the Multicenter Nephrotic Syndrome Study Network (NEPTUNE)

Barisoni, Laura; Nast, Cynthia C.; Jennette, J. Charles; Hodgin, Jeffrey B.; Herzenberg, Andrew M.; Lemley, Kevin V.; Conway, Catherine; Kopp, Jeffrey B.; Kretzler, Matthias; Lienczewski, Christa; Ávila-Casado, Carmen; Bagnasco, Serena M.; Sethi, Sanjeev; Tomaszewski, John E.; Gasim, Adil; Hewitt, Stephen M.

doi:10.2215/cjn.08370812

Cited by 91 publications

(112 citation statements)

References 23 publications

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“…Full details of the study design have been published elsewhere (2,3). Eligibility criteria include individuals of any age scheduled for a clinically indicated initial renal biopsy with proteinuria $0.5 g/d from 24-hour urine or .0.5 g/g random urine proteinto-creatinine ratio (UPC).…”

Section: Methodsmentioning

confidence: 99%

“…The major goal of the Nephrotic Syndrome Study Network (NEPTUNE) is to assemble an observational cohort with MCD, FSGS, and MN to support innovative multidisciplinary translational research and advance the field toward effective treatments (2,3). Here, we describe baseline cohort characteristics, early disease outcomes, and address the following questions: (1) What are the characteristics of proteinuric patients undergoing kidney biopsy in North America today?…”

Section: Introductionmentioning

confidence: 99%

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Complete Remission in the Nephrotic Syndrome Study Network

Gipson

Troost

Lafayette

et al. 2016

Clinical Journal of the American Society of Nephrology

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Background and objectives This analysis from the Nephrotic Syndrome Study Network (NEPTUNE) assessed the phenotypic and pathology characteristics of proteinuric patients undergoing kidney biopsy and defined the frequency and factors associated with complete proteinuria remission (CRever).Design, setting, participants, & measurements We enrolled adults and children with proteinuria $0.5 g/d at the time of first clinically indicated renal biopsy at 21 sites in North America from April 2010 to June 2014 into a prospective cohort study. NEPTUNE central pathologists assigned participants to minimal-change disease (MCD), FSGS, membranous nephropathy, or other glomerulopathy cohorts. Outcome measures for this analysis were (1) CRever with urine protein-to-creatinine ratio (UPC) ,0.3 g/g with preserved native kidney function and (2) ESRD. Continuous variables are reported as median and interquartile range (IQR; 25th, 75th percentile). Cox proportional hazards modeling was used to assess factors associated with CRever.Results We enrolled 441 patients: 116 (27%) had MCD, 142 (32%) had FSGS, 66 (15%) had membranous nephropathy, and 117 (27%) had other glomerulopathy. The baseline UPC was 4.1 g/g (IQR, 1.9, 7.7) and the eGFR was 81 ml/min per 1.73 m 2 (IQR, 50, 105). Median duration of observation was 19 months (IQR,11, 30). CRever occurred in 46% of patients, and 4.6% progressed to ESRD. Multivariate analysis demonstrated that higher prebiopsy proteinuria (hazard ratio, 0.3; 95% confidence interval, 0.2 to 0.5) and pathology diagnosis (FSGS versus MCD; hazard ratio, 0.2; 95% confidence interval, 0.1 to 0.5) were inversely associated with CRever. The effect of immunosuppressive therapy on remission varied by pathology diagnosis.Conclusions In NEPTUNE, the high frequency of other pathology in proteinuric patients affirms the value of the diagnostic kidney biopsy. Clinical factors, including level of proteinuria before biopsy, pathology diagnosis, and immunosuppression, are associated with complete remission.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Complete Remission in the Nephrotic Syndrome Study Network

Gipson

Troost

Lafayette

et al. 2016

Clinical Journal of the American Society of Nephrology

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“…33 The degree of cortical IF and TA was scored as the percentage of cortex by each reader, and the average of the scores from at least two readers was used.…”

Section: Quantitation Of If and Tamentioning

confidence: 99%

Integrative Genomics Identifies Novel Associations with APOL1 Risk Genotypes in Black NEPTUNE Subjects

Sampson

Robertson

Martini³

et al. 2016

Journal of the American Society of Nephrology

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APOL1 variants have been associated with renal phenotypes in blacks. To refine clinical outcomes and discover mechanisms of APOL1-associated kidney injury, we analyzed clinical and genomic datasets derived from 90 black subjects in the Nephrotic Syndrome Study Network (NEPTUNE), stratified by APOL1 risk genotype. Ninety subjects with proteinuria $0.5 g/d were enrolled at first biopsy for primary nephrotic syndrome and followed. Clinical outcomes were determined, and renal histomorphometry and sequencing of Mendelian nephrotic syndrome genes were performed. APOL1 variants were genotyped, and glomerular and tubulointerstitial transcriptomes from protocol renal biopsy cores were analyzed for differential and correlative gene expression. Analyses were performed under the recessive model (high-risk genotype defined by two risk alleles). APOL1 high-risk genotype was significantly associated with a 17 ml/min per 1.73 m 2 lower eGFR and a 69% reduction in the probability of complete remission at any time, independent of histologic diagnosis. Neither APOL1 risk group was enriched for Mendelian mutations. On renal biopsy, high-risk genotype was associated with increased fractional interstitial area, interstitial fibrosis, and tubular atrophy. Risk genotype was not associated with intrarenal APOL1 mRNA expression levels. Differential expression analysis demonstrated an increased steady-state level of five genes associated with the high-risk genotype (CXCL9, CXCL11, and UBD in glomerulus; SNOR14B and MUC13 in tubulointerstitium). APOL1 tubulointerstitial coexpression analysis showed coexpression of APOL1 mRNA levels with a group of intrarenal transcripts that together were associated with increased interstitial fibrosis and tubular atrophy. These data indicate the high-risk APOL1 genotype confers renal risk across histopathologic diagnoses.

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“…The rich visual information can now be captured by digital whole-slide imaging and made accessible to data mining tools used for the genetic and molecular information described above (23). These images can be accessed remotely for analysis by pathologists for systematic scoring, morphometric measurements, and potentially, computerassisted image analysis.…”

Section: Large-scale Data Capture For Structural Clinical and Envirmentioning

confidence: 99%

Defining Glomerular Disease in Mechanistic Terms: Implementing an Integrative Biology Approach in Nephrology

Mariani

Pendergraft

Kretzler

2016

CJASN

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Advances in biomedical research allow for the capture of an unprecedented level of genetic, molecular, and clinical information from large patient cohorts, where the quest for precision medicine can be pursued. An overarching goal of precision medicine is to integrate the large-scale genetic and molecular data with deep phenotypic information to identify a new mechanistic disease classification. This classification can ideally be used to meet the clinical goal of the right medication for the right patient at the right time. Glomerular disease presents a formidable challenge for precision medicine. Patients present with similar signs and symptoms, which cross the current disease categories. The diseases are grouped by shared histopathologic features, but individual patients have dramatic variability in presentation, progression, and response to therapy, reflecting the underlying biologic heterogeneity within each glomerular disease category. Despite the clinical challenge, glomerular disease has several unique advantages to building multilayered datasets connecting genetic, molecular, and structural information needed to address the goals of precision medicine in this population. Kidney biopsy tissue, obtained during routine clinical care, provides a direct window into the molecular mechanisms active in the affected organ. In addition, urine is a biofluid ideally suited for repeated measurement from the diseased organ as a liquid biopsy with potential to reflect the dynamic state of renal tissue. In our review, current approaches for large-scale data generation and integration along the genotype-phenotype continuum in glomerular disease will be summarized. Several successful examples of this integrative biology approach within glomerular disease will be highlighted along with an outlook on how achieving a mechanistic disease classification could help to shape glomerular disease research and care in the future.

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Digital Pathology Evaluation in the Multicenter Nephrotic Syndrome Study Network (NEPTUNE)

Cited by 91 publications

References 23 publications

Complete Remission in the Nephrotic Syndrome Study Network

Complete Remission in the Nephrotic Syndrome Study Network

Integrative Genomics Identifies Novel Associations with APOL1 Risk Genotypes in Black NEPTUNE Subjects

Defining Glomerular Disease in Mechanistic Terms: Implementing an Integrative Biology Approach in Nephrology

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