Reproducibility of the NEPTUNE descriptor-based scoring system on whole-slide images and histologic and ultrastructural digital images

Barisoni, Laura; Troost, Jonathan P.; Nast, Cynthia C.; Bagnasco, Serena M.; Ávila-Casado, Carmen; Hodgin, Jeffrey B.; Palmer, Matthew; Rosenberg, Avi Z.; Gasim, Adil; Chrysta, Liensziewski,; Merlino, Lino; Chien, Hui Ping; Chang, Anthony; Meehan, Shane M.; Gaut, Joseph P.; Song, Peter; Holzman, Lawrence B.; Gibson, Debbie; Kretzler, Matthias; Gillespie, Brenda W.; Hewitt, Stephen M.

doi:10.1038/modpathol.2016.58

Cited by 59 publications

(86 citation statements)

References 30 publications

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“…We also noted modest inter-rater agreement among our pathologists on AIN diagnosis and interstitial histological features. Such low inter-rater agreement, although concerning, has been reported by others in kidney biopsies from transplants (11) and glomerular disease (23). We were aware of such discordance among pathology raters and attempted to overcome this by asking multiple pathologists to review each biopsy.…”

Section: L I N I C a L M E D I C I N Ementioning

confidence: 84%

Urine TNF-α and IL-9 for clinical diagnosis of acute interstitial nephritis

Moledina¹,

Wilson²,

Pober³

et al. 2019

JCI Insight

105

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IntroductionAcute interstitial nephritis (AIN) is the cause of over 15% cases of acute loss of kidney function (1). Unlike many other causes of acute loss of kidney function, AIN is treatable. However, ongoing inflammation can lead to permanent kidney damage in AIN if it is not diagnosed and treated promptly. In fact, it is estimated that 40% to 60% of cases of AIN result in development of chronic kidney disease (CKD). Delay in diagnosis is one of the best predictors of incomplete recovery of kidney function. Recent studies estimated that at least 2% to 3% of cases of CKD could be from undiagnosed AIN from proton pump inhibitor use, a figure that is equivalent to 1 million US adults (2-5). Thus, a noninvasive biomarker for timely diagnosis of AIN could improve clinical care of patients suspected to have AIN and may reduce occurrence of CKD.A major challenge of AIN is distinguishing it from the other causes of acute rise in serum creatinine. When AIN was first described in association with β-lactam antibiotics, such as methicillin, it presented with typical features of an allergic reaction, such as onset of fever, rash, and eosinophilia, shortly after BACKGROUND. Clinical diagnosis of acute interstitial nephritis (AIN) is challenging because of lack of a diagnostic biomarker and requires a kidney biopsy. We hypothesized that AIN is mediated by specific T cell subsets such that specific T cell cytokine levels could serve as biomarkers to distinguish AIN from other causes of acute kidney disease (AKD). METHODS.We enrolled consecutive sampling participants who underwent a kidney biopsy for AKD evaluation at 2 centers between 2015 and 2018. Three pathologists independently established AIN diagnosis through review of kidney biopsies. Through univariable and multivariable analysis of 12 selected urine and plasma cytokines, we identified 2 that were diagnostic of AIN. RESULTS.Of the 218 participants, 32 (15%) were diagnosed with AIN by all 3 pathologists. Participants with AIN had consistently higher levels of urine TNF-α and IL-9 than those with other diagnoses, including acute tubular injury, glomerular diseases, and diabetic kidney disease, and those without any kidney disease. As compared with participants in the lowest quartile, we noted higher odds of AIN in participants in the highest quartiles of TNF-α levels (adjusted odds ratio, 10.9 [1.8, 65.9]) and IL-9 levels (7.5 [1.2, 45.7]) when controlling for blood eosinophils, leukocyturia, and proteinuria. Addition of biomarkers improved area under receiver operating characteristic curve over clinicians' prebiopsy diagnosis (0.84 [0.78, 0.91]) vs. 0.62 [(0.53, 0.71]) and a model of current tests (0.84 [0.76, 0.91] vs. 0.69 [0.58, 0.80]). CONCLUSIONS.Inclusion of urinary TNF-α and IL-9 improves discrimination over clinicians' prebiopsy diagnosis and currently available tests for AIN diagnosis. FUNDING.

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Section: L I N I C a L M E D I C I N Ementioning

confidence: 84%

Urine TNF-α and IL-9 for clinical diagnosis of acute interstitial nephritis

Moledina¹,

Wilson²,

Pober³

et al. 2019

JCI Insight

105

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“…In NEPTUNE biopsies, interstitial fibrosis (IF), tubular atrophy (TA), acute tubular injury (ATI) and interstitial inflammation (II) were assessed on whole-slide images as described (Barisoni et al, 2016). Glomerular, tubular, interstitial and vascular features were evaluated by up to five participating renal pathologists, and the average score was used for each feature.…”

Section: Methodsmentioning

confidence: 99%

Renal matrix Gla protein expression increases progressively with CKD and predicts renal outcome

Miyata

Nast

Dai

et al. 2018

Experimental and Molecular Pathology

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Background: Matrix Gla Protein (MGP) is a potent inhibitor of ectopic calcification and modulates bone morphogenesis. Little is known about MGP expression or function in kidney. Methods: We investigated renal MGP expression in Sprague-Dawley rats after 5/6 nephrectomy (5/6 Nx) and in human kidney biopsies in the Nephrotic Syndrome Study Network (NEPTUNE) cohort. We analyzed associations between glomerular (n = 182) and tubulointerstitial (TI) (n = 219) MGP mRNA levels and the disease activity/histologic features in NEPTUNE patients. Additionally, uncarboxylated and carboxylated MGP (ucMGP and cMGP, respectively) were localized by immunohistochemistry and quantitated in kidney tissues of patients at different stages of CKD (n = 18). Results: Renal MGP expression was increased in rats after 5/6 Nx. In NEPTUNE data, baseline estimated glomerular filtration rate (eGFR) negatively correlated with glomerular and TI MGP expression (p < 0.001). TI MGP expression strongly correlated with interstitial fibrosis, tubular atrophy, acute tubular injury, and inter-stitial inflammation, independent of eGFR. Kaplan-Meier analysis and multivariable Cox regression showed that higher levels of TI MGP expression were associated with an increased risk for the composite of 40% decline in eGFR and end-stage renal disease (ESRD) (HR, 3.31; 95% CI, 1.31 to 6.32; p =0.02). Glomerular and tubulointerstitial cells demonstrated nuclear and cytoplasmic cMGP and ucMGP staining, and eGFR inversely correlated with quantified glomerular cMGP staining (p < 0.05). Conclusions: Our data demonstrate that renal MGP expression is increased in human and experimental CKD, and is associated with renal outcome. Additional studies are needed to determine its mechanism of action.

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“…Whole slide images of glass slides from cases stored in the NEPTUNE digital pathology repository were assessed for percentage of cortex involved by IF/TA by six pathologists. The percentage of cortex involved by IF/TA was determined in each individual stain and averaged for an overall % value 56 . Cases with paired tubulointerstitial gene expression were assessed.…”

Section: Assessment Of Interstitial Fibrosis and Tubular Atrophymentioning

confidence: 99%

Inflammatory and JAK-STAT Pathways as Shared Molecular Targets for ANCA-Associated Vasculitis and Nephrotic Syndrome

Eddy

Nair

Mariani

et al. 2018

Preprint

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249 words ABSTRACT Background: Glomerular diseases of the kidney are presently differentiated, diagnosed and treated according to conventional clinical or structural features. While etiologically diverse, these diseases share common clinical features including but not limited to reduced glomerular filtration rate, increased serum creatinine and proteinuria suggesting shared pathogenic mechanisms across diseases. Renal biopsies from patients with nephrotic syndrome (NS) or ANCA-associated vasculitis (AAV) were evaluated for molecular signals cutting across conventional disease categories as candidates for therapeutic targets. Methods: Renal biopsies were obtained from patients with NS (minimal change disease, focal segmental glomerulosclerosis, or membranous nephropathy) (n=187) or AAV (granulomatosis with polyangiitis or microscopic polyangiitis) (n=80) from the Nephrotic Syndrome Study Network (NEPTUNE) and the European Renal cDNA Bank. Transcriptional profiles were assessed for shared disease mechanisms.Results: In the discovery cohort, 10-25% transcripts were differentially regulated versus healthy controls in both NS and AAV, >500 transcripts were shared across diseases. The majority of shared transcripts (60-77%) were validated in independent samples. Therapeutically targetable networks were identified, including inflammatory JAK-STAT signaling. STAT1 eQTLs were identified and STAT1 expression associated with GFRbased outcome. A transcriptional STAT1 activity score was generated from STAT1-regulated target genes which correlated with CXCL10 (p<0.001), a JAK-STAT biomarker, predictors of CKD progression, interstitial fibrosis (r=0.41, p<0.001), and urinary EGF (r=-0.51, p<0.001).Conclusion: AAV and NS caused from histopathologically distinct disease categories share common intra-renal molecular pathways cutting across conventional disease classifications. This approach provides a starting point for de novo drug development, and repurposing efforts in rare kidney diseases.

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Reproducibility of the NEPTUNE descriptor-based scoring system on whole-slide images and histologic and ultrastructural digital images

Cited by 59 publications

References 30 publications

Urine TNF-α and IL-9 for clinical diagnosis of acute interstitial nephritis

Urine TNF-α and IL-9 for clinical diagnosis of acute interstitial nephritis

Renal matrix Gla protein expression increases progressively with CKD and predicts renal outcome

Inflammatory and JAK-STAT Pathways as Shared Molecular Targets for ANCA-Associated Vasculitis and Nephrotic Syndrome

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