Interstitial fibrosis and tubular atrophy (IFTA) on a renal biopsy are strong indicators of disease chronicity and prognosis. Techniques that are typically used for IFTA grading remain manual, ...leading to variability among pathologists. Accurate IFTA estimation using computational techniques can reduce this variability and provide quantitative assessment. Using trichrome-stained whole-slide images (WSIs) processed from human renal biopsies, we developed a deep-learning framework that captured finer pathologic structures at high resolution and overall context at the WSI level to predict IFTA grade. WSIs (n = 67) were obtained from The Ohio State University Wexner Medical Center. Five nephropathologists independently reviewed them and provided fibrosis scores that were converted to IFTA grades: ≤10% (none or minimal), 11% to 25% (mild), 26% to 50% (moderate), and >50% (severe). The model was developed by associating the WSIs with the IFTA grade determined by majority voting (reference estimate). Model performance was evaluated on WSIs (n = 28) obtained from the Kidney Precision Medicine Project. There was good agreement on the IFTA grading between the pathologists and the reference estimate (κ = 0.622 ± 0.071). The accuracy of the deep-learning model was 71.8% ± 5.3% on The Ohio State University Wexner Medical Center and 65.0% ± 4.2% on Kidney Precision Medicine Project data sets. Our approach to analyzing microscopic- and WSI-level changes in renal biopsies attempts to mimic the pathologist and provides a regional and contextual estimation of IFTA. Such methods can assist clinicopathologic diagnosis.
Aims
The Oxford Classification E score (endocapillary hypercellularity) predicts renal functional decline in IgA nephropathy (IgAN) patients free from steroid/immunosuppressive (IS) therapy, but is ...poorly reproducible. We hypothesise that endocapillary hypercellularity reflects glomerular inflammation and that the presence of CD68‐positive cells is a more robust marker of E score.
Methods and results
CD68‐positive cells were quantified in glomeruli and tubulointerstitium in biopsies from 118 IgAN patients, and cell counts were correlated with the criteria of the Oxford Classification, assigned on PAS‐stained serial sections. There was a strong correlation between median glomerular CD68 count and the percentage of glomeruli showing endocapillary hypercellularity (r = 0.67; P < 0.001; r2 = 0.45), while there was no correlation between CD68‐positive cells and mesangial hypercellularity, % segmental sclerosis, % of crescents and % tubular atrophy/interstitial fibrosis (TA/IF). ROC curve analysis demonstrated that a maximum glomerular CD68 count of 6 is the best cut‐off for distinguishing E0 from E1 (sensitivity 94.1%, specificity 71%, area under the curve = 89%). Identification of biopsies with a maximum glomerular CD68‐count >6 was reproducible (kappa score 0.8), and there was a strong correlation between glomerular CD68 counts obtained by conventional light microscopy and by image analysis (r = 0.80, r2 = 0.64, P < 0.0001). Digital image analysis revealed that tubulointerstitial CD68‐positive cells correlated moderately with % TA/IF (r = 0.59, r2 = 0.35, P < 0.001) and GFR at the time of biopsy (r = 0.54, r2 = 0.29, P < 0.0001), but not with mesangial and endocapillary hypercellularity.
Conclusions
While glomerular CD68‐positive cells emerge as markers of endocapillary hypercellularity, their tubulointerstitial counterparts are associated with chronic damage.
Aim
Interpretation of retrospective clinicopathological studies of IgA nephropathy (IgAN) has been confounded by immunosuppression bias. In published validation studies of the Oxford Classification ...of IgAN, an average of 33 % of patients received non-randomised steroid and/or cytotoxic therapy. In order to determine the true impact of proliferative lesions on the natural history of IgAN, analysis of patient cohorts that have received no immunosuppression is required.
Methods
We performed a retrospective single centre study of patients with IgAN managed without immunosuppressive therapy. Biopsies were scored according to the Oxford Classification. The primary outcomes were renal survival or a rapid loss of renal function defined as a decline in eGFR of >5 ml/min/year.
Results
237 patients with IgAN were identified with a mean follow-up of 82 months. 200 had biopsies available for review, of which 156 were adequate for scoring using the Oxford Classification. 9/156 patients (5.8 %) received some immunosuppressive therapy, mostly for unrelated conditions: these were excluded. In multivariate COX regression, including histological and clinical data, the only independent predictors of time to ESRD were baseline eGFR (HR 0.96 per ml/min increase, p = 0.018), baseline proteinuria (HR 1.36 per doubling, p = 0.004) and endocapillary hypercellularity (HR 4.75 for E1 compared to E0, p < 0.001). Independent predictors of a rapid decline in eGFR were proteinuria (OR 1.45 per doubling, p = 0.006), endocapillary hypercellularity (OR 3.41 for E1 compared to E0, p = 0.025) and tubular atrophy/interstitial fibrosis (OR 8.77 for T2 compared to T0, p = 0.006).
Conclusions
In a cohort of IgAN patients receiving no immunosuppression, endocapillary proliferation and tubular atrophy/interstitial fibrosis are independent predictors of rate of loss of renal function. The lack of predictive value of E score in other clinicopathological studies is most likely a result of immunosuppression-associated bias. Our findings provide evidence to support immunosuppressive treatment of endocapillary-pattern IgAN.
Background. IgA nephropathy is defined by the presence of IgA-dominant glomerular deposits. Within this definition, there is variation in the location of IgA and the presence of other ...immunoglobulins. The Oxford classification of IgA nephropathy identifies four histological features that are independent predictors of clinical outcome but does not include immunostains. Here, we investigate the potential clinical significance of immunostaining data.
Methods. Original biopsy reports from the patients in the Oxford classification study were reviewed. The location of IgA deposits (mesangial versus mesangial + capillary wall) and the presence of IgG >trace were correlated with histological and clinical features.
Results. Original biopsy reports were available for 211 of 265 patients in the Oxford classification cohort, of which 175 included sufficient details to subclassify immunostaining findings. The presence of capillary wall IgA deposits was associated with a higher mesangial cellularity score (1.3 ± 0.6 versus 0.9 ± 0.5 for mesangial-only IgA, P = 0.007) and endocapillary proliferation (per cent of patients with any endocapillary proliferation of 62 versus 35% for mesangial-only IgA, P = 0.01). Similarly, the presence of IgG was associated with a higher mesangial cellularity score (1.2 ± 0.6 versus 0.9 ± 0.5, P = 0.03) and endocapillary proliferation (per cent of patients with endocapillary proliferation of 57 versus 31% with no IgG, P = 0.009). There was no significant association between the location of IgA or the presence of IgG and rate of loss of renal function and association between the location of IgA and renal survival although patients with these immunofluorescence findings tended to receive more immunosuppression. There was a trend towards poorer renal survival in those patients with glomerular IgG (hazard ratio of 2.1, 95% confidence interval, 1.0-4.6, P = 0.06).
Conclusions. We conclude that the location of glomerular IgA and the presence of IgG correlate with mesangial and endocapillary cellularity. This supports the role of IgG and capillary wall IgA in the development of proliferative changes in IgA nephropathy.
Tonsillectomy has been considered a treatment for IgA nephropathy (IgAN). It is aimed at removing a source of pathogens, reducing mucosa-associated lymphoid tissue and decreasing polymeric IgA ...synthesis. However, its beneficial effect is still controversial. In Asia, favorable outcomes have been claimed mostly in association with corticosteroids. In Europe, small, single-center uncontrolled studies have failed to show benefits.
The European validation study of the Oxford classification of IgAN (VALIGA) collected data from 1,147 patients with IgAN over a follow-up of 4.7 years. We investigated the outcome of progression to end-stage renal disease (ESRD) and/or 50% loss of estimated glomerular filtration rate (eGFR) and the annual loss of eGFR in 61 patients who had had tonsillectomy.
Using the propensity score, which is a logistic regression model, we paired 41 patients with tonsillectomy and 41 without tonsillectomy with similar risk of progression (gender, age, race, mean blood pressure, proteinuria, eGFR at renal biopsy, previous treatments and Oxford MEST scores). No significant difference was found in the outcome. Moreover, we performed an additional propensity score pairing 17 patients who underwent tonsillectomy after the diagnosis of IgAN and 51 without tonsillectomy with similar risk of progression at renal biopsy and subsequent treatments. No significant difference was found in changes in proteinuria, or in the renal end point of 50% reduction in GFR and/or ESRD, or in the annual loss of eGFR.
In the large VALIGA cohort of European subjects with IgAN, no significant correlation was found between tonsillectomy and renal function decline.
Current guidelines suggest treatment with corticosteroids (CS) in IgA nephropathy (IgAN) when proteinuria is persistently ≥1 g/d despite 3-6 months of supportive care and when eGFR is >50 ml/min per ...1.73 m(2). Whether the benefits of this treatment extend to patients with an eGFR≤50 ml/min per 1.73 m(2), other levels of proteinuria, or different renal pathologic lesions remains unknown. We retrospectively studied 1147 patients with IgAN from the European Validation Study of the Oxford Classification of IgAN (VALIGA) cohort classified according to the Oxford-MEST classification and medication used, with details of duration but not dosing. Overall, 46% of patients received immunosuppression, of which 98% received CS. Treated individuals presented with greater clinical and pathologic risk factors of progression. They also received more antihypertensive medication, and a greater proportion received renin angiotensin system blockade (RASB) compared with individuals without immunosuppressive therapy. Immunosuppression was associated with a significant reduction in proteinuria, a slower rate of renal function decline, and greater renal survival. Using a propensity score, we matched 184 subjects who received CS and RASB to 184 patients with a similar risk profile of progression who received only RASB. Within this group, CS reduced proteinuria and the rate of renal function decline and increased renal survival. These benefits extended to those with an eGFR≤50 ml/min per 1.73 m(2), and the benefits increased proportionally with the level of proteinuria. Thus, CS reduced the risk of progression regardless of initial eGFR and in direct proportion to the extent of proteinuria in this cohort.
Prostatic neuroendocrine manifestations encompass a heterogeneous spectrum of morphologic entities. In the era of evidence-based and precision-led treatment, distinction of biologically relevant ...clinical manifestations expanded the evolving clinical role of pathologists. Recent observations on the occurrence of hormone therapy–induced aggressive prostatic cancers with neuroendocrine features have triggered the need to refine the spectrum and nomenclature of prostatic neuroendocrine manifestations. Although the morphologic assessment still remains the basis of the diagnostic workup of prostatic neoplasms, the application of ancillary biomarkers is crucial in the accurate classification of such presentations. This review provides a diagnostic roadmap for the practicing pathologist by reviewing the characteristic morphologic, immunohistochemical, and molecular correlates of various faces of prostatic neuroendocrine manifestations.
•Terminology proposal is analogous to those of other anatomic sites.•Morphologic heterogeneity stems from genomic and microenvironmental factors.•Distinction of various manifestations requires correlation of morphology with biomarkers.•Prostatic neuroendocrine manifestations also include amphicrine carcinoma
Although IgA nephropathy (IgAN) is a common cause of glomerulonephritis in children, the absence of a method to predict disease progression limits personalized risk-based treatment decisions. The ...adult International IgAN Prediction Tool comprises two validated Cox survival models that predict a 50% decline in estimated glomerular filtration rate (eGFR) or end stage kidney disease (ESKD) using clinical risk factors and Oxford MEST histology scores. Here, we updated the Prediction Tool for use in children using a multiethnic international cohort of 1,060 children with IgAN followed into adulthood. The updated pediatric Prediction Tool had better model fit than the original adult tool with lower Akaike Information Criterion, higher R2D and similar C-statistics. However, calibration showed very poor agreement between predicted and observed risks likely due to the observed disease trajectory in children. Therefore, the Tool was updated using a secondary outcome of a 30% reduction in eGFR or ESKD, resulting in better R2D (30.3%/22.2%) and similar C-statistics (0.74/0.68) compared to the adult tool but with good calibration. The trajectory of eGFR over time in children differed from adults being highly non-linear with an increase until 18 years old followed by a linear decline similar to that of adults. A higher predicted risk was associated with a smaller increase in eGFR followed by a more rapid decline, suggesting that children at risk of a 30% decrease in eGFR will eventually experience a larger 50% decrease in eGFR when followed into adulthood. As such, these two outcomes are analogous between pediatric and adult Prediction Tools. Thus, our pediatric Prediction Tool can accurately predict the risk of a 30% decline in eGFR or ESKD in children with IgAN.
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The pediatric International IgA Nephropathy (IgAN) Prediction Tool comprises two models with and without ethnicity and is the first method to predict the risk of a 30% decline in estimated glomerular ...filtration rate (eGFR) or kidney failure in children at the time of biopsy using clinical risk factors and Oxford MEST histology scores. However, it is unknown if the Prediction Tool can be applied after a period of observation post-biopsy. Using an international multi-ethnic cohort of 947 children with IgAN, 38% of whom were followed into adulthood, the Prediction Tool was updated for use one-year after biopsy. Compared to the original pediatric Prediction Tool, the updated post-biopsy Prediction Tool had a better model fit with higher R2D (51%/50% vs 20%), significant increase in 4-year C-statistics (0.83 vs 0.73/0.69, ΔC 0.09 95% confidence interval 0.07-0.10 and ΔC 0.14 0.12-0.15) and better 4-year calibration with lower integrated calibration indices (0.74/0.54 vs 2.45/1.01). Results were similar after internal validation and when the models were applied two-years after biopsy. Trajectories of eGFR after a baseline one-year post-biopsy were non-linear and those at higher predicted risk started with a lower eGFR and experienced a more rapid decline over time. In children, eGFR had a variable rate of increase until 15-18 years old then decreased linearly with a more rapid decline in higher risk groups that was similar to young adults of comparable risk. Thus, the original pediatric Prediction Tool should be used in children at the time of biopsy, and the updated pediatric Prediction Tool should be used to revaluate risk one- or two-years after biopsy.
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