scholarly journals Deep learning identifies pathological abnormalities predictive of graft loss in kidney transplant biopsies

2021 ◽  
Author(s):  
Zhengzi Yi ◽  
Fadi Salem ◽  
Madhav C Menon ◽  
Karen Keung ◽  
Caixia Xi ◽  
...  
Keyword(s):  
Deep Learning ◽  
Interstitial Fibrosis ◽  
Periodic Acid ◽  
Graft Loss ◽  
Kidney Tissue ◽  
Tubular Atrophy ◽  
Post Transplant ◽  
Pathological Lesions ◽  
Protocol Biopsies ◽  
Tissue Compartments

Background: Interstitial fibrosis, tubular atrophy, and inflammation are major contributors to renal allograft failure. Here we seek an objective, quantitative pathological assessment of these lesions to improve predictive utility. Methods: We constructed a deep–learning–based pipeline recognizing normal vs. abnormal kidney tissue compartments and mononuclear leukocyte (MNL) infiltrates from Periodic acid–Schiff (PAS) stained slides of transplant biopsies (training: n=60, testing: n=33) that quantified pathological lesions specific for interstitium, tubules and MNL infiltration. The pipeline was applied to 789 whole slide images (WSI) from baseline (n=478, pre–implantation) and 12–month post–transplant (n=311) protocol biopsies in two independent cohorts (GoCAR: 404 patients, AUSCAD: 212 patients) of transplant recipients to correlate composite lesion features with graft loss. Results: Our model accurately recognized kidney tissue compartments and MNLs. The digital features significantly correlated with Banff scores, but were more sensitive to subtle pathological changes below the thresholds in Banff scores. The Interstitial and Tubular Abnormality Score (ITAS) in baseline samples was highly predictive of 1–year graft loss (p=2.8e–05), while a Composite Damage Score (CDS) in 12–month post–transplant protocol biopsies predicted later graft loss (p=7.3e–05). ITAS and CDS outperformed Banff scores or clinical predictors with superior graft loss prediction accuracy. High/intermediate risk groups stratified by ITAS or CDS also demonstrated significantly higher incidence of eGFR decline and subsequent graft damage. Conclusions: This deep–learning approach accurately detected and quantified pathological lesions from baseline or post–transplant biopsies, and demonstrated superior ability for prediction of post–transplant graft loss with potential application as a prevention, risk stratification or monitoring tool.

Long-term impact of CMV infection on allografts and on patient survival in renal transplant patients with protocol biopsies

2015 ◽  
Vol 309 (11) ◽  
pp. F925-F932 ◽  
Author(s):  
U. Erdbrügger ◽  
I. Scheffner ◽  
M. Mengel ◽  
A. Schwarz ◽  
H. Haller ◽  
...  
Keyword(s):  
Patient Survival ◽  
Interstitial Fibrosis ◽  
Graft Loss ◽  
Cmv Infection ◽  
Tubular Atrophy ◽  
Transplant Patients ◽  
Protocol Biopsies ◽  
Glomerular Lesions ◽  
Long Term Impact

Cytomegalovirus (CMV) infection is a frequent complication of early posttransplantation. This study examines its impact on chronic allograft changes, long-term graft loss, and patient survival. We studied 594 patients who had protocol biopsies at 6 wk, and 3 and 6 mo posttransplantation. Chronic allograft changes were evaluated according to the updated Banff classification [interstitial fibrosis/tubular atrophy (IF/TA), vascular and glomerular lesions]. Follow-up data were available for up to 10 yr. CMV infection was diagnosed in 153 of 594 patients (26%) in the first year after transplantation, mostly within the first 3 mo. Graft survival was reduced in patients with CMV ( P = 0.03) as well as the combined allograft/patient survival ( P = 0.008). Prevalence of IF/TA at 6 wk after transplantation was already threefold higher in patients who experienced CMV infection later on compared with patients without CMV ( P = 0.005). In multivariate analyses, CMV viremia or disease was not a significant factor for graft loss or death. In conclusion, patients with CMV infection posttransplantation show more chronic allograft changes early on, even before CMV infection, and development of IF/TA is not more prevalent in patients with CMV. Our data do not support a significant role of CMV in patient and graft outcomes.

scholarly journals Long-term results of protocol kidney biopsy directing steroid withdrawal in simultaneous pancreas-kidney transplant patients

2018 ◽  
Vol 12 (6) ◽  
pp. 188-92 ◽  
Author(s):  
Nemin Zhu ◽  
Neal E. Rowe ◽  
Paul R. Martin ◽  
Sean S. Luke ◽  
Thomas B. McGregor ◽  
...  
Keyword(s):  
Interstitial Fibrosis ◽  
Long Term Results ◽  
Steroid Withdrawal ◽  
Tubular Atrophy ◽  
Post Transplant ◽  
Transplant Patients ◽  
Protocol Biopsies ◽  
Pancreas Function ◽  
Simultaneous Pancreas Kidney ◽  
One Year

Introduction: We sought to determine whether protocol biopsies could be used to guide treatment and improve outcomes in simultaneous pancreas-kidney (SPK) patients.Methods: Between 2004 and 2013, protocol biopsies were performed on SPK patients at 3–6 months and one year post-transplant. Maintenance immunosuppression consisted of a calcineurin inhibitor, anti-proliferative agent, and corticosteroid. Corticosteroid was withdrawn in negative early biopsies, maintained in subclinical/ borderline biopsies, and increased if Banff IB or greater rejection was identified. Endpoints included presence of interstitial fibrosis and tubular atrophy on biopsy at one year (IF/TA), rejection episodes, and renal and pancreas function at five years’ followup.Results: Forty-one SPK transplant patients were reviewed and a total of 75 protocol biopsies were identified. On early biopsy, 51% had negative biopsies, 44% had borderline rejection, and 5% had subclinical rejection. Renal and pancreas function were not significantly different at one, two, and five years post-transplant between negative vs. borderline early biopsy patients. No difference in the degree of IF/TA was found between these two groups.Conclusions: To our knowledge, this is the first study to evaluate protocol biopsies as an investigative tool prior to steroid withdrawal in SPK patients. Our study suggests that there are no detrimental functional or histological effects at five years post-transplant, despite weaning steroids in the negative biopsy group.

Automatic Evaluation of Histological Prognostic Factors Using Two Consecutive Convolutional Neural Networks on Kidney Samples

2021 ◽  
pp. CJN.07830621
Author(s):  
Elise Marechal ◽  
Adrien Jaugey ◽  
Georges Tarris ◽  
Michel Paindavoine ◽  
Jean Seibel ◽  
...  
Keyword(s):  
Neural Networks ◽  
Convolutional Neural Networks ◽  
Interstitial Fibrosis ◽  
Kidney Tissue ◽  
Area Under The Curve ◽  
Tubular Atrophy ◽  
Prognostic Features ◽  
Glomerular Volume ◽  
Luminal Stenosis ◽  
Histological Data

Background and Objectives: The prognosis of patients undergoing kidney tumor resection or kidney donation is linked to many histological criteria. These criteria notably include glomerular density, glomerular volume, vascular luminal stenosis, and severity of interstitial fibrosis/tubular atrophy. Automated measurements through a Deep Learning approach could save time and provide more precise data. This work aimed to develop a free tool to automatically obtain kidney histological prognostic features. Design, setting, participants, and measurements: Two hundred and forty one samples of healthy kidney tissue were split into 3 independent cohorts. The "Training" cohort (n=65) was used to train two Convolutional Neural Networks: one to detect the cortex and a second one to segment the kidney structures. The "Test" cohort (n=50) assessed their performances by comparing manually outlined regions of interest to predicted ones. The "Application" cohort (n=126) compared prognostic histological data obtained manually or through the algorithm based on the combination of the two Convolutional Neural Networks. Results: In the Test cohort, the networks isolated the cortex and segmented the elements of interest with good performances (more than 90% of the cortex, healthy tubules, glomeruli, and even globally sclerotic glomeruli were detected). In the Application cohort, the expected and predicted prognostic data were significantly correlated. The correlation coefficients r were respectively 0.85 for glomerular volume, 0.51 for glomerular density, 0.75 for interstitial fibrosis, 0.71 for tubular atrophy, and 0.73 for vascular intimal thickness. The algorithm had a good ability to predict significant (> 25%) tubular atrophy and interstitial fibrosis level (ROC curve with an area under the curve 0.92 and 0.91, respectively) or a significant vascular luminal stenosis (> 50%) (area under the curve 0.85). Conclusion: This freely available tool enables the automated segmentation of kidney tissue to obtain prognostic histological data in a fast, objective, reliable and reproducible way.

MiR-32-5p knockdown inhibits epithelial to mesenchymal transition and renal fibrosis by targeting SMAD7 in diabetic nephropathy

2020 ◽  
pp. 096032712095215
Author(s):  
H-J Wang ◽  
H Liu ◽  
Y-H Lin ◽  
S-J Zhang
Keyword(s):  
Diabetic Nephropathy ◽  
Renal Fibrosis ◽  
Epithelial Mesenchymal Transition ◽  
Interstitial Fibrosis ◽  
Kidney Tissue ◽  
Luciferase Reporter ◽  
Luciferase Reporter Gene ◽  
Tubular Atrophy ◽  
Mesenchymal Transition ◽  
Gene Assay

Diabetic nephropathy (DN) is primary cause of end-stage renal disease. A previous study has shown that miR-32-5p (miR-32) is highly expressed in kidney tissue during chronic allograft dysfunction with interstitial fibrosis and tubular atrophy. However, the role of miR-32-5p (miR-32) in DN is still unclear. In this study, streptozotocin-induced DN rat models and high glucose (HG)-incubated human kidney proximal tubular epithelial (HK-2) cells were established to investigate the role and underlying mechanisms of miR-32 in DN. Results of real-time PCR revealed that miR-32 levels were greatly increased in DN rats and HG-incubated HK-2 cells. Downregulation of miR-32 effectively relieved HG-induced autophagy suppression, fibrosis, epithelial-mesenchymal transition (EMT) and inflammation in HK-2 cells. Besides, miR-32 overexpression significantly down-regulated the expression of mothers against decapentaplegic homolog 7 (SMAD7), whereas knockdown of miR-32 markedly up-regulated the level of SMAD7. Dual-luciferase reporter gene assay confirmed that SMAD7 was a target of miR-32. Reintroduction of SMAD7 expression rescued miR-32-induced HK-2 cells autophagy suppression, EMT and renal fibrosis. Our findings indicate that miR-32 may play roles in the progression of EMT and fibrosis in DN.

scholarly journals Intragraft Expression of the IL-10 Gene Is Up-Regulated in Renal Protocol Biopsies with Early Interstitial Fibrosis, Tubular Atrophy, and Subclinical Rejection

2010 ◽  
Vol 176 (4) ◽  
pp. 1696-1704 ◽  
Author(s):  
Miguel Hueso ◽  
Estanis Navarro ◽  
Francesc Moreso ◽  
Francisco O'Valle ◽  
Mercè Pérez-Riba ◽  
...  
Keyword(s):  
Interstitial Fibrosis ◽  
Tubular Atrophy ◽  
Protocol Biopsies ◽  
Subclinical Rejection

Expression of pro- and antifibrotic genes in protocol biopsies from renal allografts with interstitial fibrosis and tubular atrophy

2008 ◽  
Vol 69 (06) ◽  
pp. 408-416 ◽  
Author(s):  
M. Mengel ◽  
O. Bock ◽  
M. Priess ◽  
H. Haller ◽  
H. Kreipe ◽  
...  
Keyword(s):  
Interstitial Fibrosis ◽  
Tubular Atrophy ◽  
Renal Allografts ◽  
Protocol Biopsies

scholarly journals Long-Term Outcomes in 831 Kidney Transplant Recipients with 20 Years of Graft Function

2021 ◽  
Vol 8 ◽  
Author(s):  
Varvara Kirchner ◽  
Kristen Gillingham ◽  
Oscar Serrano ◽  
Srinath Chinnakotla ◽  
Ty Dunn ◽  
...  
Keyword(s):  
Kidney Transplant ◽  
Graft Survival ◽  
Interstitial Fibrosis ◽  
Graft Loss ◽  
Graft Function ◽  
Solid Organ ◽  
Kidney Transplant Recipients ◽  
Long Term Outcomes ◽  
Tubular Atrophy

An understanding of long-term outcomes for kidney transplant(KTx) recipients who survive with graft function beyond a specific time posttransplant is the first step in creating protocols to optimize care for current and improve outcomes for future recipients. We studied 831KTx recipients-580 living donor(LD); 251 deceased donor(DD)—with graft survival(GS) >20 years.  For primary LD recipients, 25-year patient survival(PS) was 83%; 35-year, 59%.  Their 25-year death-censored graft survival(DCGS) was 89%; 35-year, 72%.   DD recipients had lower PS(P<0.01), DCGS(P<0.01).   After 20 years, two major causes of graft loss(GL) were death with function(DwF)(58%, LD; 58%, DD) and interstitial fibrosis and tubular atrophy(IFTA)(22%, LD; 23%, DD).  Two major causes of DwF were cancer(31%, LD; 31%, DD) and cardiovascular disease(CVD)(19%, LD;17%, DD).  Per multivariate analysis(MVA), risk factors for GL after 20 years in pre–calcineurin inhibitor(CNI) era were human leukocyte antigen(HLA) mismatches >3 antigens, pretransplant type 1 diabetes mellitus(DM1); in CNI era, a history of rejection, female gender.  New comorbidities after 20 years were common: CVD(13%, non-DM1;18%, DM1), infections(27%, non-DM1;37%, DM1), 20-29 years posttransplant.  Cancer after 20 years included: nonmelanotic skin cancer,22%; solid organ,7%; post-transplant lymphoproliferative disease(PTLD),2%.  To improve long-term outcomes, clinical trials on prevention, recognition, and treatment of new comorbidities are needed.

scholarly journals P1741TACROLIMUS FAST METABOLIZERS SHOW A HIGHER PROGRESSION OF INTERTITIAL FIBROSIS AND TUBULAR ATROPHY DURING THE FIRST YEAR AFTER RENAL TRASPLANTATION

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Betty Chamoun Huacon ◽  
Irina Torres ◽  
Alejandra Gabaldon ◽  
Néstor Toapanta ◽  
Joana Sellares ◽  
...  
Keyword(s):  
Interstitial Fibrosis ◽  
Univariate Analysis ◽  
First Year ◽  
Prolonged Release ◽  
Dose Ratio ◽  
Tubular Atrophy ◽  
Protocol Biopsies ◽  
The Difference ◽  
Independent Association ◽  
Allograft Loss

Abstract Background and Aims Fast tacrolimus metabolizers (expressed as the blood concentration/ dose ratio; C / D; ng / mL * mg) showed poorer renal function at 2 years, a higher incidence of nephrotoxicity and BK polyomavirus infection. Greater variability of tacrolimus trough levels (CV) from six to twelve months is associated with the appearance of HLA antibodies, interstitial fibrosis / tubular atrophy (IFTA) progression and allograft loss. We evaluate the relationship between C / D, CV and IFTA progression. Method We evaluated a cohort of 87 low immunological risk renal transplants treated with prolonged-release tacrolimus, mycophenolate mofetil and steroids. We analyzed paired protocol biopsies at 4 and 18 months. Biopsies were evaluated according to the Banff classification and the progression of IFTA was defined as the difference of ci + ct score&gt; 0 between 18 and 4 months. The C / D ratio was calculated as the average of the value recorded at 3, 6 and 12 months of follow-up. The tacrolimus CV between 6 and 12 months was calculated using all the available determinations. Results IFTA progression was observed in 36 cases (41%). In the univariate analysis, it was found that the progression of IFTA was associated with the ci + ct score at 4 months (0.92 ± 0.94 for progressors vs. 1.89 ± 1.26 not progressors, p = 0.0003), and with the average of the C / D ratio (1.70 ± 0.73 for progressors vs. 2.28 ± 1.25 not progressors; p = 0.0144, table 1). An independent association between the C/D ratio and the progression of IFTA was observed in the multivariate analysis (OR: 0.42; 95% CI: 0.22-0.82, p = 0.027). Conclusion The results of our work suggest that fast tacrolimus metabolizers (lower C / D ratio) are more susceptible to the nephrotoxic effect of tacrolimus.

scholarly journals Transcriptome changes in renal allograft protocol biopsies at 3 months precede the onset of interstitial fibrosis/tubular atrophy (IF/TA) at 6 months

2009 ◽  
Vol 24 (8) ◽  
pp. 2567-2575 ◽  
Author(s):  
Andreas Scherer ◽  
Wilfried Gwinner ◽  
Michael Mengel ◽  
Torsten Kirsch ◽  
Friedrich Raulf ◽  
...  
Keyword(s):  
Renal Allograft ◽  
Interstitial Fibrosis ◽  
Tubular Atrophy ◽  
Protocol Biopsies

Effect of resveratrol on tubular damage and interstitial fibrosis in kidneys of rats exposed to cigarette smoke

2009 ◽  
Vol 25 (8) ◽  
pp. 539-544 ◽  
Author(s):  
Meltem Kuruş ◽  
Murat Ugras ◽  
Mukaddes Esrefoglu
Keyword(s):  
Cigarette Smoke ◽  
Interstitial Fibrosis ◽  
Periodic Acid ◽  
Control Group ◽  
Albino Rats ◽  
Tubular Damage ◽  
Tubular Atrophy ◽  
Hydropic Degeneration ◽  
Group 4 ◽  
Group 2

The aim of this study was to evaluate the effect of resveratrol on kidney tissue of rats exposed to cigarette smoke. Forty adult male Wistar Albino rats were divided into four groups. Animals in group 1 was the control group. For 6 weeks, group 2 was exposed to cigarette smoke; group 3 received daily intraperitoneal injections of resveratrol (10 mg/kg/d); and group 4 was exposed to both cigarette smoke and intraperitoneal resveratrol. All rats were sacrificed with cervical dislocation. The kidney tissues were obtained, fixed in Bouin’s fixative and embeded in paraffin blocks. Samples were sectioned to 4-5 microns thickness, stained with hematoxylin/eosin (H/E), Masson’s trichromic, periodic acid-schiff (PAS) and were examined by light microscopy for tubular injury and interstitial fibrosis. Results were compared by non-parametric tests. Hydropic degeneration, tubular atrophy, tubulo-interstitial fibrosis, interstitial cell infiltration, vacuolar degeneration and desquamation were prominent in group 2. In group 4, hydropic degeneration, epithelial cell vacuolization and desquamation was not observed, but occasional tubular atrophy and dilation were observed. Our study suggests that, some morphological alterations in the rat kidney, due to cigarette smoke may be prevented by resveratrol.

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