RESUMO
Gene expression profiling from formalin-fixed paraffin-embedded (FFPE) renal allograft biopsies is a promising approach for feasibly providing a molecular diagnosis of rejection. However, large-scale studies evaluating the performance of models using NanoString platform data to define molecular archetypes of rejection are lacking. We tested a diverse retrospective cohort of over 1400 FFPE biopsy specimens, rescored according to Banff 2019 criteria and representing 10 of 11 United Network of Organ Sharing regions, using the Banff Human Organ Transplant panel from NanoString and developed a multiclass model from the gene expression data to assign relative probabilities of 4 molecular archetypes: No Rejection, Antibody-Mediated Rejection, T Cell-Mediated Rejection, and Mixed Rejection. Using Least Absolute Shrinkage and Selection Operator regularized regression with 10-fold cross-validation fitted to 1050 biopsies in the discovery cohort and technically validated on an additional 345 biopsies, our model achieved overall accuracy of 85% in the discovery cohort and 80% in the validation cohort, with ≥75% positive predictive value for each class, except for the Mixed Rejection class in the validation cohort (positive predictive value, 53%). This study represents the technical validation of the first model built from a large and diverse sample of diagnostic FFPE biopsy specimens to define and classify molecular archetypes of histologically defined diagnoses as derived from Banff Human Organ Transplant panel gene expression profiling data.
Assuntos
Nefropatias , Transplante de Rim , Transplante de Órgãos , Humanos , Transplante de Rim/efeitos adversos , Estudos de Coortes , Estudos Retrospectivos , Rejeição de Enxerto/diagnóstico , Rejeição de Enxerto/genética , Nefropatias/patologia , Expressão Gênica , Biópsia , Rim/patologiaRESUMO
BACKGROUND AND AIMS: No endoscopic scoring system has been established for immune-mediated colitis (IMC). This study aimed to establish such a system for IMC and explore its utility in guiding future selective immunosuppressive therapy (SIT) use compared to clinical symptoms. METHODS: This retrospective, international, 14-center study included 674 patients who developed IMC after immunotherapy and underwent endoscopic evaluation. Ten endoscopic features were selected by group consensus and assigned 1 point each to calculate an IMC endoscopic score (IMCES). IMCES cutoffs were chosen to maximize specificity for SIT use. This specificity was compared between IMCESs, and clinical symptoms were graded according to a standardized instrument. RESULTS: A total of 309 (45.8%) patients received SIT. IMCES specificity for SIT use was 82.8% with a cutoff of 4. The inclusion of ulceration as a mandatory criterion resulted in higher specificity (85.0% for a cutoff of 4). In comparison, the specificity of a Mayo endoscopic subscore of 3 was 74.6%, and the specificity of clinical symptom grading was much lower at 27.4% and 12.3%, respectively. Early endoscopy was associated with timely SIT use (P < .001; r = 0.4084). CONCLUSIONS: This is the largest multicenter study to devise an endoscopic scoring system to guide IMC management. An IMCES cutoff of 4 has a higher specificity for SIT use than clinical symptoms, supporting early endoscopic evaluation for IMC.
Assuntos
Colite , Colonoscopia , Índice de Gravidade de Doença , Humanos , Estudos Retrospectivos , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Colite/patologia , Colonoscopia/métodos , Imunossupressores/uso terapêutico , Idoso , Imunoterapia/métodos , Sensibilidade e Especificidade , Úlcera/patologiaRESUMO
BACKGROUND: In single-center studies, both preterm birth and low birth weight (LBW) are associated with worse outcomes in childhood nephrotic syndrome. Using the Nephrotic Syndrome Study Network (NEPTUNE) observational cohort, we tested the hypothesis that in patients with nephrotic syndrome, hypertension, proteinuria status, and disease progression would be more prevalent and more severe in subjects with LBW and prematurity singly or in combination (LBW/prematurity). METHODS: Three hundred fifty-nine adults and children with focal segmental glomerulosclerosis (FSGS) or minimal change disease (MCD) and available birth history were included. Estimated glomerular filtration rate (eGFR) decline and remission status were primary outcomes, and secondary outcomes were kidney histopathology, kidney gene expression, and urinary biomarkers. Logistic regression was used to identify associations with LBW/prematurity and these outcomes. RESULTS: We did not find an association between LBW/prematurity and remission of proteinuria. However, LBW/prematurity was associated with greater decline in eGFR. This decline in eGFR was partially explained by the association of LBW/prematurity with APOL1 high-risk alleles, but the association remained after adjustment. There were no differences in kidney histopathology or gene expression in the LBW/prematurity group compared to normal birth weight/term birth. CONCLUSION: LBW and premature babies who develop nephrotic syndrome have a more rapid decline in kidney function. We did not identify clinical or laboratory features that distinguished the groups. Additional studies in larger groups are needed to fully ascertain the effects of (LBW) and prematurity alone or in combination on kidney function in the setting of nephrotic syndrome.
Assuntos
Glomerulosclerose Segmentar e Focal , Síndrome Nefrótica , Nascimento Prematuro , Feminino , Humanos , Criança , Recém-Nascido , Adulto , Síndrome Nefrótica/complicações , Estudos de Coortes , Peso ao Nascer , Netuno , Nascimento Prematuro/epidemiologia , Recém-Nascido de Baixo Peso , Glomerulosclerose Segmentar e Focal/patologia , Proteinúria/etiologia , Proteinúria/complicações , Apolipoproteína L1/genéticaRESUMO
CCR5 KO kidney transplant (KTx) recipients are extraordinarily high alloantibody producers and develop pathology that mimics human antibody-mediated rejection (AMR). C57BL/6 and CCR5 KO mice (H-2b ) were transplanted with A/J kidneys (H-2a ); select cohorts received adoptive cell therapy (ACT) with alloprimed CXCR5+ CD8+ T cells (or control cells) on day 5 after KTx. ACT efficacy was evaluated by measuring posttransplant alloantibody, pathology, and allograft survival. Recipients were assessed for the quantity of CXCR5+ CD8+ T cells and CD8-mediated cytotoxicity to alloprimed IgG+ B cells. Alloantibody titer in CCR5 KO recipients was four-fold higher than in C57BL/6 recipients. The proportion of alloprimed CXCR5+ CD8+ T cells 7 days after KTx in peripheral blood, lymph node, and spleen was substantially lower in CCR5 KO compared to C57BL/6 recipients. In vivo cytotoxicity towards alloprimed IgG+ B cells was also reduced six-fold in CCR5 KO recipients. ACT with alloprimed CXCR5+ CD8+ T cells (but not alloprimed CXCR5- CD8+ or third-party primed CXCR5+ CD8+ T cells) substantially reduced alloantibody titer, ameliorated AMR pathology, and prolonged allograft survival. These results indicate that a deficiency in quantity and function of alloprimed CXCR5+ CD8+ T cells contributes to high alloantibody and AMR in CCR5 KO recipient mice, which can be rescued with ACT.
Assuntos
Transplante de Rim , Animais , Linfócitos T CD8-Positivos , Rejeição de Enxerto/patologia , Imunoglobulina G , Isoanticorpos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos KnockoutRESUMO
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.
Assuntos
Aprendizado Profundo , Interpretação de Imagem Assistida por Computador/métodos , Nefropatias/diagnóstico , Nefropatias/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia , Criança , Pré-Escolar , Feminino , Fibrose , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
Inconsistencies in the preparation of histology slides and whole-slide images (WSIs) may lead to challenges with subsequent image analysis and machine learning approaches for interrogating the WSI. These variabilities are especially pronounced in multicenter cohorts, where batch effects (i.e. systematic technical artifacts unrelated to biological variability) may introduce biases to machine learning algorithms. To date, manual quality control (QC) has been the de facto standard for dataset curation, but remains highly subjective and is too laborious in light of the increasing scale of tissue slide digitization efforts. This study aimed to evaluate a computer-aided QC pipeline for facilitating a reproducible QC process of WSI datasets. An open source tool, HistoQC, was employed to identify image artifacts and compute quantitative metrics describing visual attributes of WSIs to the Nephrotic Syndrome Study Network (NEPTUNE) digital pathology repository. A comparison in inter-reader concordance between HistoQC aided and unaided curation was performed to quantify improvements in curation reproducibility. HistoQC metrics were additionally employed to quantify the presence of batch effects within NEPTUNE WSIs. Of the 1814 WSIs (458 H&E, 470 PAS, 438 silver, 448 trichrome) from n = 512 cases considered in this study, approximately 9% (163) were identified as unsuitable for subsequent computational analysis. The concordance in the identification of these WSIs among computational pathologists rose from moderate (Gwet's AC1 range 0.43 to 0.59 across stains) to excellent (Gwet's AC1 range 0.79 to 0.93 across stains) agreement when aided by HistoQC. Furthermore, statistically significant batch effects (p < 0.001) in the NEPTUNE WSI dataset were discovered. Taken together, our findings strongly suggest that quantitative QC is a necessary step in the curation of digital pathology cohorts. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Assuntos
Interpretação de Imagem Assistida por Computador/métodos , Nefropatias/diagnóstico , Patologia Cirúrgica/métodos , Controle de Qualidade , Algoritmos , Biópsia , Humanos , Interpretação de Imagem Assistida por Computador/normas , Patologia Cirúrgica/normasRESUMO
AIM: Allograft rejection is a serious concern in heart transplant medicine. Though endomyocardial biopsy with histological grading is the diagnostic standard for rejection, poor inter-pathologist agreement creates significant clinical uncertainty. The aim of this investigation is to demonstrate that cellular rejection grades generated via computational histological analysis are on-par with those provided by expert pathologists. METHODS AND RESULTS: The study cohort consisted of 2472 endomyocardial biopsy slides originating from three major US transplant centres. The 'Computer-Assisted Cardiac Histologic Evaluation (CACHE)-Grader' pipeline was trained using an interpretable, biologically inspired, 'hand-crafted' feature extraction approach. From a menu of 154 quantitative histological features relating the density and orientation of lymphocytes, myocytes, and stroma, a model was developed to reproduce the 4-grade clinical standard for cellular rejection diagnosis. CACHE-grader interpretations were compared with independent pathologists and the 'grade of record', testing for non-inferiority (δ = 6%). Study pathologists achieved a 60.7% agreement [95% confidence interval (CI): 55.2-66.0%] with the grade of record, and pair-wise agreement among all human graders was 61.5% (95% CI: 57.0-65.8%). The CACHE-Grader met the threshold for non-inferiority, achieving a 65.9% agreement (95% CI: 63.4-68.3%) with the grade of record and a 62.6% agreement (95% CI: 60.3-64.8%) with all human graders. The CACHE-Grader demonstrated nearly identical performance in internal and external validation sets (66.1% vs. 65.8%), resilience to inter-centre variations in tissue processing/digitization, and superior sensitivity for high-grade rejection (74.4% vs. 39.5%, P < 0.001). CONCLUSION: These results show that the CACHE-grader pipeline, derived using intuitive morphological features, can provide expert-quality rejection grading, performing within the range of inter-grader variability seen among human pathologists.
Assuntos
Tomada de Decisão Clínica , Transplante de Coração , Aloenxertos , Biópsia , Rejeição de Enxerto , Humanos , IncertezaRESUMO
The application of deep learning for automated segmentation (delineation of boundaries) of histologic primitives (structures) from whole slide images can facilitate the establishment of novel protocols for kidney biopsy assessment. Here, we developed and validated deep learning networks for the segmentation of histologic structures on kidney biopsies and nephrectomies. For development, we examined 125 biopsies for Minimal Change Disease collected across 29 NEPTUNE enrolling centers along with 459 whole slide images stained with Hematoxylin & Eosin (125), Periodic Acid Schiff (125), Silver (102), and Trichrome (107) divided into training, validation and testing sets (ratio 6:1:3). Histologic structures were manually segmented (30048 total annotations) by five nephropathologists. Twenty deep learning models were trained with optimal digital magnification across the structures and stains. Periodic Acid Schiff-stained whole slide images yielded the best concordance between pathologists and deep learning segmentation across all structures (F-scores: 0.93 for glomerular tufts, 0.94 for glomerular tuft plus Bowman's capsule, 0.91 for proximal tubules, 0.93 for distal tubular segments, 0.81 for peritubular capillaries, and 0.85 for arteries and afferent arterioles). Optimal digital magnifications were 5X for glomerular tuft/tuft plus Bowman's capsule, 10X for proximal/distal tubule, arteries and afferent arterioles, and 40X for peritubular capillaries. Silver stained whole slide images yielded the worst deep learning performance. Thus, this largest study to date adapted deep learning for the segmentation of kidney histologic structures across multiple stains and pathology laboratories. All data used for training and testing and a detailed online tutorial will be publicly available.
Assuntos
Aprendizado Profundo , Biópsia , Corantes , Rim , Córtex Renal/diagnóstico por imagemRESUMO
Kidney failure is common in patients with Coronavirus Disease-19 (COVID-19), resulting in increased morbidity and mortality. In an international collaboration, 284 kidney biopsies were evaluated to improve understanding of kidney disease in COVID-19. Diagnoses were compared to five years of 63,575 native biopsies prior to the pandemic and 13,955 allograft biopsies to identify diseases that have increased in patients with COVID-19. Genotyping for APOL1 G1 and G2 alleles was performed in 107 African American and Hispanic patients. Immunohistochemistry for SARS-CoV-2 was utilized to assess direct viral infection in 273 cases along with clinical information at the time of biopsy. The leading indication for native biopsy was acute kidney injury (45.4%), followed by proteinuria with or without concurrent acute kidney injury (42.6%). There were more African American patients (44.6%) than patients of other ethnicities. The most common diagnosis in native biopsies was collapsing glomerulopathy (25.8%), which was associated with high-risk APOL1 genotypes in 91.7% of cases. Compared to the five-year biopsy database, the frequency of myoglobin cast nephropathy and proliferative glomerulonephritis with monoclonal IgG deposits was also increased in patients with COVID-19 (3.3% and 1.7%, respectively), while there was a reduced frequency of chronic conditions (including diabetes mellitus, IgA nephropathy, and arterionephrosclerosis) as the primary diagnosis. In transplants, the leading indication was acute kidney injury (86.4%), for which rejection was the predominant diagnosis (61.4%). Direct SARS-CoV-2 viral infection was not identified. Thus, our multi-center large case series identified kidney diseases that disproportionately affect patients with COVID-19 and demonstrated a high frequency of APOL1 high-risk genotypes within this group, with no evidence of direct viral infection within the kidney.
Assuntos
Injúria Renal Aguda , COVID-19 , Apolipoproteína L1/genética , Humanos , Rim , Estudos Retrospectivos , SARS-CoV-2RESUMO
AIMS: Immune checkpoint inhibitors (ICIs) have revolutionised the treatment of advanced malignancies by boosting immune-mediated destruction of neoplastic cells, but are associated with side effects stemming from generalised immune system activation against normal tissues. Checkpoint ligand expression in non-tumoral cells of tissues affected by immune-related adverse effects has been described in ICI-associated hypophysitis, myocarditis, and acute interstitial nephritis. We aimed to investigate the tissue expression of the immune checkpoint receptor programmed cell death-1 (PD-1) and its ligand, programmed death-ligand 1 (PD-L1), in PD-1 inhibitor-associated colitis (PD1i colitis). METHODS AND RESULTS: PD-1 and PD-L1 immunohistochemical expression levels were analysed in 15 cases of PD1i colitis and potential mimics-infectious colitis and inflammatory bowel disease (IBD). Increased epithelial expression of PD-L1 was observed in PD1i colitis as compared with normal colon and infectious colitis, but the expression level was lower than that in IBD. Conversely, PD-1 expression in inflammatory cells was higher in infectious colitis, intermediate in IBD, and minimal or absent in normal colon and in patients receiving PD-1 inhibitors. CONCLUSIONS: Although our results do not justify the use of PD-L1 as a discriminatory marker of PD1i colitis against other entities within the differential diagnosis, they support the concept that PD1i colitis and IBD have similar pathogenetic mechanisms. They also highlight the fact that PD-L1 epithelial overexpression is a commonly used mechanism of the gastrointestinal tract mucosa to protect itself from inflammatory-mediated damage resulting from different aetiologies, which probably underpins the high incidence of gastrointestinal immune-related adverse effects in patients receiving ICI therapies, in whom this mechanism is disrupted.
Assuntos
Antígeno B7-H1/metabolismo , Colite/diagnóstico , Receptor de Morte Celular Programada 1/metabolismo , Colite/tratamento farmacológico , Colite/fisiopatologia , Diagnóstico Diferencial , Feminino , Trato Gastrointestinal/metabolismo , Trato Gastrointestinal/patologia , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Imuno-Histoquímica , Doenças Inflamatórias Intestinais , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Primary immunoglobulin A nephropathy (IgAN) is characterized by IgA1-dominant or codominant glomerular deposits, postulated to be galactose deficient (Gd). However, glomerular IgA deposition can also occur in nonrenal diseases such as liver cirrhosis, psoriasis and inflammatory bowel disease ('secondary IgAN') or be an incidental finding in biopsies with other pathologies. A glomerulonephritis resembling IgAN can develop in patients with bacterial, mainly staphylococcal infections [staphylococcal infection-associated glomerulonephritis (SAGN)]. There are no specific histological features to distinguish between these, but differentiation is critical for appropriate management. The aim of this study was to investigate whether a recently described antibody to Gd-IgA1 (KM-55) could aid in differentiating primary IgAN from other conditions with glomerular IgA deposition, especially SAGN. METHODS: We performed a retrospective cohort study of patients who underwent kidney biopsy for clinical indications and were found to have glomerular IgA deposits. RESULTS: We evaluated 100 biopsies, including primary IgAN (n = 44), secondary IgAN (n = 27), SAGN (n = 13), incidental IgA deposition (n = 8) and lupus nephritis (n = 8). There was no difference in Gd-IgA staining intensity or the proportion of positive cases between primary and secondary IgAN. SAGN and cases with incidental IgA deposits had significantly lower Gd-IgA staining intensity than primary IgAN, but up to 69% of SAGN cases were positive (albeit weaker). CONCLUSIONS: Gd-IgA staining is present not only in primary IgAN, but also in biopsies with secondary IgAN, SAGN and incidental IgA. Weak or negative staining may favor SAGN, especially in the setting of infection, or incidental IgA in the absence of nephritic symptoms or in the presence of other unrelated glomerular pathologies. However, positive staining for Gd-IgA alone is not specific enough for a diagnosis of primary IgAN.
Assuntos
Galactose/deficiência , Glomerulonefrite por IGA/diagnóstico , Imunoglobulina A/imunologia , Cirrose Hepática/diagnóstico , Nefrite Lúpica/diagnóstico , Psoríase/diagnóstico , Coloração e Rotulagem/métodos , Adolescente , Adulto , Idoso , Biópsia , Criança , Diagnóstico Diferencial , Feminino , Glomerulonefrite por IGA/sangue , Glomerulonefrite por IGA/imunologia , Humanos , Imunoglobulina A/sangue , Cirrose Hepática/sangue , Cirrose Hepática/imunologia , Nefrite Lúpica/sangue , Nefrite Lúpica/imunologia , Masculino , Pessoa de Meia-Idade , Psoríase/sangue , Psoríase/imunologia , Estudos Retrospectivos , Adulto JovemRESUMO
BACKGROUND: Pathologic diagnosis of monoclonal gammopathy (MIg)-associated kidney disease requires specific morphologic and immunofluorescence (IF) findings with deposits on electron microscopy. We have encountered kidney biopsies showing only diffuse "background" monoclonal light chain staining, without characteristic morphologic or ultrastructural findings. Such staining is often overlooked if weak, or over-diagnosed as MIg-associated kidney disease if strong, causing dilemma over the need for immediate clone-directed therapy. We performed a clinicopathologic study to better understand its significance. MATERIALS AND METHODS: Database search revealed 32 such cases over 12 years. Demographic, laboratory, and pathology data were retrieved along with a mean follow-up of 13 months. RESULTS: 15/32 (47%) patients did have active myeloma on hematologic testing (without myeloma casts) warranting immediate clone-directed therapy; but 11/32 (34%) did not develop active myeloma; 3/32 (9%) did not even have detectable paraprotein; 3/32 (9%) were lost to follow-up. Importantly, strong background light chain staining was seen even in some non-myeloma biopsies and conversely, weak staining was seen in some myeloma biopsies, complicating diagnosis. CONCLUSION: It is important to recognize and document this finding in the biopsy report, but by itself, it should not be classified as MIg-associated kidney disease even in the face of strong staining intensity. A thorough hematologic work-up is critically important to unmask underlying active myeloma, which many patients may have. But equally important is to avoid inadvertent clone-directed therapy in patients who do not have active myeloma despite the background monoclonal staining. A protocol for periodic monitoring with hematologic and renal parameters to watch for possible malignant transformation is recommend for timely implementation of therapy to minimize renal damage.
Assuntos
Nefropatias/patologia , Rim/patologia , Paraproteinemias/patologia , Humanos , Estudos RetrospectivosRESUMO
Terminal complement inhibition therapy with eculizumab (a humanized monoclonal antibody to C5) has revolutionized the treatment of patients with thrombotic microangiopathy (TMA). Successful responders are often placed on long-standing therapy to prevent disease recurrence in the native kidney or allograft. The tissue deposition of eculizumab in patients with C3 glomerulopathy has been described but no studies have yet investigated tissue deposition of eculizumab in cases where it was indicated for thrombotic microangiopathy which, unlike C3 glomerulopathy, does not usually show immune-type electron dense deposits. To evaluate this, we reviewed biopsies from 13 patients who received eculizumab for TMA treatment or prevention of recurrence. We found IgG2, IgG4, and kappa positivity within arterioles corresponding to eculizumab deposits, with similar distribution to C5b-9, in all but one patient. In that patient eculizumab therapy had been discontinued 24 months prior to biopsy. Deposits in arterioles could be seen as early as one day after infusion and after a single dose of eculizumab, and were detected up to 162 days after therapy discontinuation. This may play a role in controlling local complement activation-associated vascular changes in these patients. Thus, IgG subclass staining by immunofluorescence is important to avoid misdiagnoses of immune-complex or monoclonal immunoglobulin deposition disease in patients with TMA who received eculizumab.
Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Arteríolas/patologia , Inativadores do Complemento/farmacologia , Rim/patologia , Microangiopatias Trombóticas/tratamento farmacológico , Adulto , Idoso , Anticorpos Monoclonais Humanizados/uso terapêutico , Biópsia , Ativação do Complemento/efeitos dos fármacos , Inativadores do Complemento/uso terapêutico , Complexo de Ataque à Membrana do Sistema Complemento/antagonistas & inibidores , Complexo de Ataque à Membrana do Sistema Complemento/metabolismo , Feminino , Humanos , Rim/irrigação sanguínea , Masculino , Pessoa de Meia-Idade , Recidiva , Estudos Retrospectivos , Prevenção Secundária/métodos , Microangiopatias Trombóticas/patologiaRESUMO
BACKGROUND: Proliferative glomerulonephritis with monoclonal IgG deposits (PGNMIGD) is a disease entity classified under the group of "Monoclonal gammopathy-related kidney diseases", and can recur after transplant. Clinical remission of proteinuria in patients with PGNMIGD has been previously shown following anti-B cell and/or anti-plasma cell therapies. Our case is the first to show complete histologic resolution of the glomerular monoclonal IgG kappa deposits in a case of recurrent PGNMIGD in renal allograft after rituximab and steroid treatment. This is a novel finding and it shows that the deposits are amenable to therapy. This case also highlights the importance of IgG subclass staining in the recognition of the monoclonal nature of the deposits. It is particularly important in PGNMIGD because only 20 to 30% of patients with this disease are reported to have detectable monoclonal gammopathy, and the deposits do not have any organized substructure on electron microscopic examination. Morphologically, they resemble polyclonal immune-type deposits seen in other immune complex glomerulonephritides such as lupus nephritis, infection-associated glomerulonephritis, and membranoproliferative glomerulonephritis (MPGN type I). CASE PRESENTATION: The patient is a 44 year old Caucasian male who received a living unrelated donor kidney transplant for end-stage renal disease diagnosed 7 years before transplant. The reported native kidney biopsy diagnosis was membranoproliferative glomerulonephritis (MPGN) with IgG, C3 and kappa restricted deposits. Fourteen months post-transplant, he presented with abrupt worsening of graft function, proteinuria and serum IgG kappa monoclonal spike. Allograft biopsy was consistent with recurrent PGNMIGD, considering the native kidney diagnosis and interval post-transplant. He underwent plasmapheresis, IV pooled immune globulin, steroid pulse and taper, and anti-CD-20 Rituximab therapy. Patient had gradual decline in proteinuria and complete resolution of the immune deposits on repeat biopsy 3 months later. Unfortunately he subsequently developed chronic antibody-mediated rejection and transplant glomerulopathy and graft failure 34 months post-transplant. CONCLUSIONS: In a transplant setting, repeat allograft biopsies are frequently performed for graft dysfunction. This provides a good opportunity to study the evolution of the immune deposits following treatment. Our case shows complete histologic resolution of the deposits in allograft PGNMIGD.
Assuntos
Anticorpos Monoclonais/análise , Glomerulonefrite Membranoproliferativa/patologia , Imunoglobulina G/análise , Imunossupressores/uso terapêutico , Glomérulos Renais/patologia , Paraproteinemias/patologia , Rituximab/uso terapêutico , Corticosteroides/uso terapêutico , Adulto , Biópsia por Agulha , Terapia Combinada , Glomerulonefrite Membranoproliferativa/tratamento farmacológico , Glomerulonefrite Membranoproliferativa/imunologia , Rejeição de Enxerto/tratamento farmacológico , Rejeição de Enxerto/terapia , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Falência Renal Crônica/etiologia , Falência Renal Crônica/terapia , Glomérulos Renais/química , Transplante de Rim , Doadores Vivos , Masculino , Paraproteinemias/tratamento farmacológico , Paraproteinemias/imunologia , Plasmaferese , Recidiva , Doadores não RelacionadosRESUMO
Percutaneous biopsy is a key diagnostic tool for both native and allograft kidney diseases. Adequacy criteria vary, but at a minimum, a biopsy should allow the pathologist to reach a diagnosis and provide prognostic information such as the degree of interstitial fibrosis and tubular atrophy (IF/TA) and percentage of glomerulosclerosis. Whereas most studies use glomerular counts as a surrogate for biopsy adequacy, the amount and preservation of tubulointerstitium is equally important, considering IF/TA is a major prognostic parameter for most medical renal diseases. Many studies have compared the diagnostic adequacy of different gauge needles; however few have investigated performance differences between same gauge needles. In this study, we retrospectively analyzed 235 renal biopsies performed at a single center in Canada over 2years to compare the utilization, safety, diagnostic and prognostic performance of two 18-gauge needles in native and allograft kidney biopsies. We found no significant difference in needle utilization between native and allograft kidneys, or between trainees and staff radiologists. The total tissue yielded area, glomerular counts, percentage of inadequate biopsies and number of passes were similar; however the number of cases in which IF/TA evaluation was deemed not possible was higher for biopsies using disposable instrument needles (4.3% vs. 0%; p=0.01). These also showed greater number of tissue fragments (median 4 for reusable vs 3 for disposable; p=0.04). We postulate that the increased tissue fragmentation might have impaired the pathologists ability to accurately assess interstitial fibrosis and tubular atrophy in biopsies obtained with the disposable instrument needles.
Assuntos
Biópsia por Agulha , Nefropatias/patologia , Rim/patologia , Agulhas , Adulto , Aloenxertos , Biópsia por Agulha/métodos , Feminino , Humanos , Nefropatias/diagnóstico , Transplante de Rim/métodos , Masculino , Pessoa de Meia-Idade , Nefrectomia/métodos , Estudos Retrospectivos , Transplante Homólogo/métodosAssuntos
Rejeição de Enxerto/terapia , Isoanticorpos/efeitos adversos , Falência Renal Crônica/cirurgia , Transplante de Rim/efeitos adversos , Cromossomo Filadélfia , Complicações Pós-Operatórias/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Feminino , Taxa de Filtração Glomerular , Rejeição de Enxerto/etiologia , Rejeição de Enxerto/patologia , Sobrevivência de Enxerto , Transplante de Células-Tronco Hematopoéticas , Humanos , Imunossupressores/uso terapêutico , Testes de Função Renal , Pessoa de Meia-Idade , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/patologia , Prognóstico , Indução de Remissão , Fatores de Risco , Doadores de Tecidos/provisão & distribuição , Transplante HomólogoRESUMO
Pheochromocytomas and paragangliomas are neuroendocrine tumors shown to be responsive to multitargeted tyrosine kinase inhibitor (TKI) treatment. Despite growing knowledge regarding their genetic basis, the ability to predict behavior in these tumors remains challenging. There is also limited knowledge of their tyrosine kinase receptor expression and whether the clinical response observed to the TKI sunitinib relates only to its anti-angiogenic properties or also due to a direct effect on tumor cells. To answer these questions, an in vitro model of sunitinib treatment of a pheochromocytoma cell line was created. Sunitinib targets (VEGFRs, PDGFRs, and C-KIT), FGFRs, and cell cycle regulatory proteins were investigated in human tissue microarrays. SDHB immunohistochemistry was used as a surrogate marker for the presence of succinate dehydrogenase mutations. The FGFR4 G388R single nucleotide polymorphism was also investigated. Sunitinib treatment in vitro decreases cell proliferation mainly by targeting cell cycle, DNA metabolism, and cell organization genes. FGFR1, -2, and -4, VEGFR2, PDGFRα, and p16 were overexpressed in primary human pheochromocytomas and paragangliomas. Discordant results were observed for VEGFR1, p27, and p21 overexpressed in paragangliomas but underexpressed in pheochromocytomas; PDGFRß, Rb, and Cyclin D1 overexpressed in paragangliomas only; and FGFR3 overexpressed in pheochromocytomas and underexpressed in paragangliomas. Low expression of C-KIT, p53, and Aurora kinase A and B was observed. Nuclear FGFR2 expression was associated with increased risk of metastasis (odds ratio (OR)=7.61, P=0.008), as was membranous PDGFRα (OR=13.71, P=0.015), membranous VEGFR1 (OR=8.01, P=0.037), nuclear MIB1 (OR=1.26, P=0.008), and cytoplasmic p27 (OR=1.037, P=0.030). FGFR3, VEGFR2, and C-KIT levels were associated with decreased risk of metastasis. We provide new insights into the mechanistic actions of sunitinib in pheochromocytomas and paragangliomas, and support current evidence that multitargeted TKIs might be a suitable treatment alternative for these tumors.
Assuntos
Neoplasias das Glândulas Suprarrenais/enzimologia , Antineoplásicos/farmacologia , Biomarcadores Tumorais/metabolismo , Indóis/farmacologia , Terapia de Alvo Molecular , Paraganglioma/enzimologia , Feocromocitoma/enzimologia , Inibidores de Proteínas Quinases/farmacologia , Pirróis/farmacologia , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Neoplasias das Glândulas Suprarrenais/genética , Neoplasias das Glândulas Suprarrenais/patologia , Adulto , Animais , Apoptose/efeitos dos fármacos , Biomarcadores Tumorais/antagonistas & inibidores , Biomarcadores Tumorais/genética , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Desenho de Fármacos , Feminino , Humanos , Imuno-Histoquímica , Masculino , Camundongos , Pessoa de Meia-Idade , Mutação , Paraganglioma/tratamento farmacológico , Paraganglioma/genética , Paraganglioma/patologia , Feocromocitoma/tratamento farmacológico , Feocromocitoma/genética , Feocromocitoma/patologia , Polimorfismo de Nucleotídeo Único , Proteínas Proto-Oncogênicas c-kit/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-kit/metabolismo , Receptores Proteína Tirosina Quinases/genética , Receptores Proteína Tirosina Quinases/metabolismo , Receptor Tipo 4 de Fator de Crescimento de Fibroblastos/genética , Receptores do Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Receptores do Fator de Crescimento Derivado de Plaquetas/metabolismo , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptores de Fatores de Crescimento do Endotélio Vascular/metabolismo , Succinato Desidrogenase/genética , Succinato Desidrogenase/metabolismo , Sunitinibe , Análise Serial de TecidosRESUMO
Background: Kidney biopsy is the gold-standard for diagnosing medical renal diseases, but the accuracy of the diagnosis greatly depends on the quality of the biopsy specimen, particularly the amount of renal cortex obtained. Inadequate biopsies, characterized by insufficient cortex or predominant medulla, can lead to inconclusive or incorrect diagnoses, and repeat biopsy. Unfortunately, there has been a concerning increase in the rate of inadequate kidney biopsies, and not all medical centers have access to trained professionals who can assess biopsy adequacy in real time. In response to this challenge, we aimed to develop a machine learning model capable of assessing the percentage cortex of each biopsy pass using smartphone images of the kidney biopsy tissue at the time of biopsy. Methods: 747 kidney biopsy cores and corresponding smartphone macro images were collected from five unused deceased donor kidneys. Each core was imaged, formalin-fixed, sectioned, and stained with Periodic acid-Schiff (PAS) to determine cortex percentage. The fresh unfixed core images were captured using the macro camera on an iPhone 13 Pro. Two experienced renal pathologists independently reviewed the PAS-stained sections to determine the cortex percentage. For the purpose of this study, the biopsies with less than 30% cortex were labeled as inadequate, while those with 30% or more cortex were classified as adequate. The dataset was divided into training (n=643), validation (n=30), and test (n=74) sets. Preprocessing steps involved converting High-Efficiency Image Container iPhone format images to JPEG, normalization, and renal tissue segmentation using a U-Net deep learning model. Subsequently, a classification deep learning model was trained on the renal tissue region of interest and corresponding class label. Results: The deep learning model achieved an accuracy of 85% on the training data. On the independent test dataset, the model exhibited an accuracy of 81%. For inadequate samples in the test dataset, the model showed a sensitivity of 71%, suggesting its capability to identify cases with inadequate cortical representation. The area under the receiver-operating curve (AUC-ROC) on the test dataset was 0.80. Conclusion: We successfully developed and tested a machine learning model for classifying smartphone images of kidney biopsies as either adequate or inadequate, based on the amount of cortex determined by expert renal pathologists. The model's promising results suggest its potential as a smartphone application to assist real-time assessment of kidney biopsy tissue, particularly in settings with limited access to trained personnel. Further refinements and validations are warranted to optimize the model's performance.
RESUMO
The escalating incidence of kidney biopsies providing insufficient tissue for diagnosis poses a dual challenge, straining the healthcare system and jeopardizing patients who may require rebiopsy or face the prospect of an inaccurate diagnosis due to an unsampled disease. Here, we introduce a web-based tool that can provide real-time, quantitative assessment of kidney biopsy adequacy directly from photographs taken with a smartphone camera. The software tool was developed using a deep learning-driven automated segmentation technique, trained on a dataset comprising nephropathologist-confirmed annotations of the kidney cortex on digital biopsy images. Our framework demonstrated favorable performance in segmenting the cortex via 5-fold cross-validation (Dice coefficient: 0.788±0.130) (n=100). Offering a bedside tool for kidney biopsy adequacy assessment has the potential to provide real-time guidance to the physicians performing medical kidney biopsies, reducing the necessity for re-biopsies. Our tool can be accessed through our web-based platform: http://www.biopsyadequacy.org.
RESUMO
Introduction: Antibrush border antibody disease (ABBA) is an autoimmune tubulointerstitial kidney disease that primarily affects older individuals and results in progressive kidney failure. It is rare with only 20 reported cases. Here, we describe a case series to further define the clinicopathologic spectrum and natural history, and to inform management. Methods: We identified 67 patients with ABBA who underwent kidney biopsy, including 65 native and 2 transplants. Demographics, clinical findings, and laboratory data were obtained. Histopathologic data included light microscopy, immunofluorescence, electron microscopy and immunostaining for LRP2, CUBN, and AMN. Follow-up data, including treatment(s), laboratory values, and outcomes, were available from 51 patients. Results: Patients with ABBA were predominantly male with a median age of 72 years. Median serum creatinine was 2.7 mg/dl, proteinuria was 2.8 g/day, and hematuria was present in two-thirds of the patients. Tubular injury with LRP2-positive tubular basement membrane (TBM) deposits were seen in 94.2% of patients. Thirty-eight patients (56.7%) had a second kidney disease, commonly glomerular diseases with high-grade proteinuria. These diseases included podocytopathies, membranous nephropathy (MN), IgA nephropathy, diabetic glomerulopathy, lupus nephritis (LN), crescentic glomerulonephritis (GN), tubulointerstitial nephritis, and involvement by lymphoma. The majority of patients were treated with immunosuppression. Of those patients with follow-up, 29.4% achieved remission, 70.6% had no response, and 52.8% required dialysis or were deceased. Untreated patients were at the highest risk. Conclusion: ABBA is a rare autoimmune kidney disease that often occurs with other kidney diseases. Although the overall prognosis of ABBA is poor, there is potential benefit from immunosuppression.