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Primary membranous nephropathy is a leading cause of adult nephrotic syndrome. The field took a major step forward with the identification of phospholipase A2 receptor (PLA2R) as a target antigen in the majority of cases and with the ability to measure circulating autoantibodies to PLA2R. Since then, the existence of additional target antigens such as thrombospondin type-1 domain-containing 7A, exostosin 1 and 2, neural EGFL like 1, and semaphorin 3B has been demonstrated. The ability to detect and monitor levels of circulating autoantibodies has opened a new window onto the humoral aspect of primary membranous nephropathy. Clinicians now rely on clinical parameters such as proteinuria, as well as levels of circulating autoantibodies against PLA2R and the results of immunofluorescence staining for PLA2R within kidney biopsy tissue, to guide the management of this disease. The relationship between immunologic and clinical disease course is consistent, but not necessarily intuitive. In addition, kidney biopsy provides only a single snapshot of disease that needs to be interpreted in light of changing clinical and serological findings. A clear understanding of these dynamic parameters is essential for staging, treatment, and management of this disease. This review aims to shed light on current knowledge regarding the development and time course of changes in the serum levels of autoantibodies against PLA2R, proteinuria, and histological findings that underlie the pathophysiology of primary membranous nephropathy.

In the United States, many low-income patients initiating hemodialysis are uninsured before qualifying for Medicare. Inadequate access to predialysis care may delay their arteriovenous (AV) access creation and increase tunneled dialysis catheter (TDC) use. The 2014 Affordable Care Act expanded eligibility for Medicaid among low-income adults, but not every state adopted this measure. We evaluated whether Medicaid expansion was associated with decreased TDC use for hemodialysis initiation.We queried the United States Vascular Quality Initiative state-level database for non-Medicare patients undergoing initial AV access creation from 2011 to 2018. We evaluated associations of receiving initial AV access in states that expanded Medicaid with concurrent TDC use, survival, and insurance coverage.Data were available for patients in 31 states: 19 states expanded Medicaid from January 2014 to February 2015. Among 8462 patients in the postexpansion period from March 2015 to December 2018, 58% were in Medicaid expansion states. Patients in Medicaid expansion states less often had concurrent TDCs (40% vs. 48%, P0.001). In multivariable analysis, Medicaid expansion was independently associated with fewer TDCs (OR 0.7, 95% CI 0.6-0.8, P0.001). Three-year survival was similar between patients in Medicaid expansion and nonexpansion states (84.7% vs. 85.2%, P = 0.053). Multivariable cox-regression confirmed the finding (HR 0.95, 95% CI 0.82-1.1, P = 0.482). In difference-in-differences analysis, Medicaid expansion was associated with a 9.2-percentage point increase in Medicaid coverage (95% CI 2.7-15.8, P = 0.009). Hispanic patients exhibited a 30.1-percentage point increase in any insurance coverage (95% CI 0.3-59.9, P = 0.048).Patients in Medicaid expansion states were less likely to have TDCs during initial AV access creation, suggesting earlier predialysis care. Hispanic patients benefited from increased insurance coverage. Expanding insurance options for the underserved may improve quality metrics and cost-savings for hemodialysis patients.

Murine models are employed to probe various aspects of peritoneal dialysis (PD), such as peritoneal inflammation and fibrosis. These events drive peritoneal membrane failure in humans, which remains an area of intense investigation due to its profound clinical implications in managing patients with end-stage kidney disease (ESKD). Despite the clinical importance of PD and its related complications, current experimental murine models suffer from key technical challenges that compromise the models' performance. These include PD catheter migration and kinking and usually warrant earlier catheter removal. These limitations also drive the need for a greater number of animals to complete a study. Addressing these drawbacks, this study introduces technical improvements and surgical nuances to prevent commonly observed PD catheter complications in a murine model. Moreover, this modified model is validated by inducing peritoneal inflammation and fibrosis using lipopolysaccharide injections. In essence, this paper describes an improved method to create an experimental model of PD.

Purpose of review The current review highlights advances in the use of direct-acting antiviral (DAA) agents in the treatment of hepatitis C virus (HCV) in chronic kidney disease (CKD) stages G4-5, end-stage renal disease, and kidney transplantation. The use of DAA to facilitate kidney transplantation of HCV negative recipients with kidneys from HCV-infected donors and in the management of HCV-related cryoglobulinemia are also reviewed. Recent findings DAA treatment results in rates of viral clearance (sustained virological response or SVR) of 90-100% in all studied CKD populations, comparable to SVR rates in the general population. DAA treatment allows safe and effective transplantation of HCV viremic kidneys into uninfected recipients. Summary The high SVR results achieved with DAA allow successful treatment of previously under-treated CKD populations, and encouraged innovative interventions such as the use of HCV-infected donor kidneys to uninfected kidney transplant recipients.

Reactivation of BK virus (BKV) remains a dreaded complication in immunosuppressed states. Conventionally, BKV is known as a cause for BKV-associated nephropathy and allograft dysfunction in kidney transplant recipients. However, emerging studies have shown its negative impact on native kidney function and patient survival in other transplants and its potential role in diseases such as cancer. Because BKV-associated nephropathy is driven by immunosuppression, reduction in the latter is a convenient standard of care. However, this strategy is risk prone due to the development of donor-specific antibodies affecting long-term allograft survival. Despite its pathogenic role, there is a distinct lack of effective anti-BKV therapeutics. This limitation combined with increased morbidity and health care cost of BKV-associated diseases add to the complexity of BKV management. While summarizing recent advances in the pathogenesis of BKV-associated nephropathy and its reactivation in other organ transplants, this review illustrates the limitations of current and emerging therapeutic options and provides a compelling argument for an effective targeted anti-BKV drug.

A male college student presented to the emergency department with altered mental status and a serum ethanol level higher than the hospital laboratory assay. His course was complicated by mechanical ventilation, vasopressors, and cardiotoxicity. Thirteen hours into admission and despite aggressive supportive measures, the patient remained obtunded off sedation with serum ethanol level elevated at 428 mg/dL. A decision was made to initiate hemodialysis to expedite ethanol clearance and prevent further end-organ damage. Two hours into hemodialysis, mental status improved and serum ethanol level had decreased to 264 mg/dL. A total of 4 hours of hemodialysis were completed and serum ethanol level continued to downtrend. Dialysis increased the rate of ethanol elimination by a factor of 4 and prevented further cardiotoxicity or electrolyte level abnormalities. This case supports the use of hemodialysis for adult patients who meet the criteria of severe ethanol toxicity requiring critical care resources and having evidence of organ toxicity to 1 or more organ.

Chronic kidney disease (CKD) imposes a strong and independent risk for peripheral artery disease (PAD). While solutes retained in CKD patients (uremic solutes) inflict vascular damage, their role in PAD remains elusive. Here, we show that the dietary tryptophan-derived uremic solutes including indoxyl sulfate (IS) and kynurenine (Kyn) at concentrations corresponding to those in CKD patients suppress β-catenin in several cell types, including microvascular endothelial cells (ECs), inhibiting Wnt activity and proangiogenic Wnt targets in ECs. Mechanistic probing revealed that these uremic solutes downregulated β-catenin in a manner dependent on serine 33 in its degron motif and through the aryl hydrocarbon receptor (AHR). Hindlimb ischemia in adenine-induced CKD and IS solute–specific mouse models showed diminished β-catenin and VEGF-A in the capillaries and reduced capillary density, which correlated inversely with blood levels of IS and Kyn and AHR activity in ECs. An AHR inhibitor treatment normalized postischemic angiogenic response in CKD mice to a non-CKD level. In a prospective cohort of PAD patients, plasma levels of tryptophan metabolites and plasma’s AHR-inducing activity in ECs significantly increased the risk of future adverse limb events. This work uncovers the tryptophan metabolite/AHR/β-catenin axis as a mediator of microvascular rarefaction in CKD patients and demonstrates its targetability for PAD in CKD models.

The current review highlights advances in the use of direct-acting antiviral (DAA) agents in the treatment of hepatitis C virus (HCV) in chronic kidney disease (CKD) stages G4-5, end-stage renal disease, and kidney transplantation. The use of DAA to facilitate kidney transplantation of HCV negative recipients with kidneys from HCV-infected donors and in the management of HCV-related cryoglobulinemia are also reviewed.DAA treatment results in rates of viral clearance (sustained virological response or SVR) of 90-100% in all studied CKD populations, comparable to SVR rates in the general population. DAA treatment allows safe and effective transplantation of HCV viremic kidneys into uninfected recipients.The high SVR results achieved with DAA allow successful treatment of previously under-treated CKD populations, and encouraged innovative interventions such as the use of HCV-infected donor kidneys to uninfected kidney transplant recipients.

Background: The number of glomeruli on a kidney biopsy slide followed by glomerular assessment constitute as standard components of a renal pathology report. The prevailing method for glomerular identification and assessment remains manual, labor intensive and non-standardized. In the era of digitized kidney biopsies, an automated method to identify, segment and count glomeruli is highly desirable. Methods and results: We developed an automated method to detect and segment the glomeruli within digitized kidney biopsy images by leveraging a deep learning architecture based on convolutional neural networks (CNN). A total of 275 trichrome-stained images (Average image size: 2560x1920x3 pixels, 1-2 unique images per patient, Scale: 0.85 μm/pixel) processed at 40x magnification from renal biopsies of 171 chronic kidney disease patients treated at the Boston Medical Center from 2009-2012 were analyzed. A sliding window operation was defined to crop each 40x image to smaller images of size 300x300x3 pixels. Each cropped image was then evaluated by clinical experts to identify the presence of a unique glomerulus, and each identified glomerulus was included in the training dataset (n = 751). About the same number of cropped images, containing the non-glomerular regions of the kidney biopsy, served as control cases. The CNN model was constructed as a binary classification problem to discriminate glomerular images from the non-glomerular ones (Performance on test data - Accuracy: 97.47±0.31%; Sensitivity: 96.43±1.89%; Specificity: 98.76±1.44%). Using the trained CNN model, another sliding window operator was developed to scan the digitized biopsies. A heatmap was generated to highlight regions of intensity that the CNN model classified as glomerular regions. Subsequently, two independent image processing strategies, one using steps such as image binarization and image erosion, and the other using image binarization, distance transform and watershed segmentation, were performed on the heatmaps to generate discriminatory signatures of the identified glomeruli. The final step involved automatically drawing a box around the higher intensity areas leading to output images with segmented glomerular regions (Performance on test data - Accuracy: 99.97±0.0086%; Sensitivity: 54.37±0.23%; Specificity: 99.99±0.009%). Conclusion: While used in the context of nephropathology, this study demonstrates the power of artificial intelligence to assess complex histologic structures and identify structural variations. Adoption of such methods of counting and classifying glomeruli using standard histological staining without disturbing the workflow can expedite the assessment of slides by the pathologists and serve as a first step toward more comprehensive automated analysis.

There are numerous case reports and a handful of single1–5 center studies reporting on COVID‐19 in kidney transplant recipients. Most reports arise from the epicenters of where the SARS‐CoV‐2 virus was first detected such as New York City1,2,5 and Europe3,4. We in UNOS Region 1 experienced COVID‐19 weeks to a month later and questioned whether our experience was different. The programs within UNOS Region 1 have had a long history of sharing information in an attempt to mitigate the effect of viruses on our patients.

PURPOSE Cancer patients are at a higher risk of venous thromboembolism (VTE) than the general population. In the general population, blacks are at a higher risk of VTE compared with whites. The influence of race on cancer-associated VTE remains unexplored. We examined whether black cancer patients are at a higher risk of VTE and whether these differences are present in specific cancer types. DESIGN A retrospective study was performed in the largest safety net hospital of New England using a cohort of cancer patients characterized by a substantial number of nonwhites. RESULTS We identified 16,498 subjects with solid organ and hematologic malignancies from 2004 to 2018. Among them, we found 186 unique incident VTE events, of which the majority of the events accrued within the first 2 years of cancer diagnosis. Overall, blacks showed a 3-fold higher incidence of VTE (1.8%) compared with whites (0.6%; P

The proto-oncogene β-catenin drives colorectal cancer (CRC) tumorigenesis. Casitas B-lineage lymphoma (c-Cbl) inhibits CRC tumor growth through targeting nuclear β-catenin by a poorly understood mechanism. In addition, the role of c-Cbl in human CRC remains largely underexplored. Using a novel quantitative histopathologic technique, we demonstrate that patients with high c-Cbl-expressing tumors had significantly better median survival (3.7 years) compared with low c-Cbl-expressing tumors (1.8 years; P = 0.0026) and were more than twice as likely to be alive at 3 years compared with low c-Cbl tumors (P = 0.0171). Our data further demonstrate that c-Cbl regulation of nuclear β-catenin requires phosphorylation of c-Cbl Tyr371 because its mutation compromises its ability to target β-catenin. The tyrosine 371 (Y371H) mutant interacted with but failed to ubiquitinate nuclear β-catenin. The nuclear localization of the c-Cbl-Y371H mutant contributed to its dominant negative effect on nuclear β-catenin. The biological importance of c-Cbl-Y371H was demonstrated in various systems, including a transgenic Wnt-8 zebrafish model. c-Cbl-Y371H mutant showed augmented Wnt/β-catenin signaling, increased Wnt target genes, angiogenesis, and CRC tumor growth. This study demonstrates a strong link between c-Cbl and overall survival of patients with CRC and provides new insights into a possible role of Tyr371 phosphorylation in Wnt/β-catenin regulation, which has important implications in tumor growth and angiogenesis in CRC.

Hepatitis C virus (HCV) infection is prevalent in patients with kidney disease including transplant candidates and recipients. It is associated with increased morbidity and mortality in end-stage renal disease patients and also increases the risk of allograft rejection and decreases allograft and patient survival post-transplant. Newly developed direct acting antivirals have revolutionized the way HCV is treated. Whether patients are treated before or after kidney transplantation, the cure rates with direct acting antivirals are >90%. Great debate has formed revolving the optimal timing to treat kidney transplant candidates. On the one hand, treatment before transplantation decreases early post-transplant complications related to HCV. On the other, postponing treatment until after transplantation opens the possibility of transplanting a kidney from a HCV positive donor, which is associated with shorter waiting time and improved organ utilization by expanding the organ donor pool. Most patients living in an area where waiting time is reduced by accepting an HCV positive kidney would benefit by the strategy of treatment post-transplantation, but this decision needs to be individualized in a patient-by-patient basis given that there are special circumstances (i.e., severe HCV-related extrahepatic manifestations, availability of live donors, etc.) in which treatment before transplant might be preferred.

Hepatitis C virus (HCV) is a common cause of increased morbidity and mortality in kidney transplant patients. It is associated with posttransplant glomerulonephritis, chronic allograft nephropathy, and New Onset Diabetes after Transplant (NODAT). In the past, HCV was difficult to treat due to the presence of interferon alpha-based therapies that were difficult to tolerate and were associated with adverse side-effects, such as the risk of rejection. With the advent of oral directly acting antiviral therapies, the landscape for HCV and transplantation has changed. These agents are highly effective and well tolerated with minimal side-effects. Sustained viral response rates in excess of 90% are achieved with most current treatment regimens active against all HCV genotypes. These new agents may show an improvement in graft and patient survival while essentially eliminating the risk of acute rejection from the use of prior interferon-based HCV therapies. These agents may also result in an improvement in organ allocation for HCV donor/HCV recipient transplantation. This review is meant to discuss the epidemiology of HCV, the new oral direct-acting antiviral agents (DAAs) and future opportunities for research in the field of HCV related transplantation.

Introduction Chronic kidney damage is routinely assessed semiquantitatively by scoring the amount of fibrosis and tubular atrophy in a renal biopsy sample. Although image digitization and morphometric techniques can better quantify the extent of histologic damage, we need more widely applicable ways to stratify kidney disease severity. Methods We leveraged a deep learning architecture to better associate patient-specific histologic images with clinical phenotypes (training classes) including chronic kidney disease (CKD) stage, serum creatinine, and nephrotic-range proteinuria at the time of biopsy, and 1-, 3-, and 5-year renal survival. Trichrome-stained images processed from renal biopsy samples were collected on 171 patients treated at the Boston Medical Center from 2009 to 2012. Six convolutional neural network (CNN) models were trained using these images as inputs and the training classes as outputs, respectively. For comparison, we also trained separate classifiers using the pathologist-estimated fibrosis score (PEFS) as input and the training classes as outputs, respectively. Results CNN models outperformed PEFS across the classification tasks. Specifically, the CNN model predicted the CKD stage more accurately than the PEFS model (κ = 0.519 vs. 0.051). For creatinine models, the area under curve (AUC) was 0.912 (CNN) versus 0.840 (PEFS). For proteinuria models, AUC was 0.867 (CNN) versus 0.702 (PEFS). AUC values for the CNN models for 1-, 3-, and 5-year renal survival were 0.878, 0.875, and 0.904, respectively, whereas the AUC values for PEFS model were 0.811, 0.800, and 0.786, respectively. Conclusion The study demonstrates a proof of principle that deep learning can be applied to routine renal biopsy images.

Individuals with CKD are particularly predisposed to thrombosis after vascular injury. Using mouse models, we recently described indoxyl sulfate, a tryptophan metabolite retained in CKD and an activator of tissue factor (TF) through aryl hydrocarbon receptor (AHR) signaling, as an inducer of thrombosis across the CKD spectrum. However, the translation of findings from animal models to humans is often challenging. Here, we investigated the uremic solute-AHR-TF thrombosis axis in two human cohorts, using a targeted metabolomics approach to probe a set of tryptophan products and high-throughput assays to measure AHR and TF activity. Analysis of baseline serum samples was performed from 473 participants with advanced CKD from the Dialysis Access Consortium Clopidogrel Prevention of Early AV Fistula Thrombosis trial. Participants with subsequent arteriovenous thrombosis had significantly higher levels of indoxyl sulfate and kynurenine, another uremic solute, and greater activity of AHR and TF, than those without thrombosis. Pattern recognition analysis using the components of the thrombosis axis facilitated clustering of the thrombotic and nonthrombotic groups. We further validated these findings using 377 baseline samples from participants in the Thrombolysis in Myocardial Infarction II trial, many of whom had CKD stage 2-3. Mechanistic probing revealed that kynurenine enhances thrombosis after vascular injury in an animal model and regulates thrombosis in an AHR-dependent manner. This human validation of the solute-AHR-TF axis supports further studies probing its utility in risk stratification of patients with CKD and exploring its role in other diseases with heightened risk of thrombosis.

Introduction: Monoclonal Ig deposition disease (MIDD) frequently leads to kidney failure, and a large proportion of these patients would greatly benefit from kidney transplantation. However, data on kidney transplantation outcomes in MIDD are limited. Methods: This was a retrospective analysis of long-term renal outcomes of 23 patients with MIDD, including 6 patients who underwent kidney transplantation. Results: The 1-, 5-, and 10-year overall survival (OS) from diagnosis were 95%, 78%, and 65%, respectively. Approximately half of the patients (n = 12) progressed to end-stage renal disease (ESRD) with a median time from diagnosis to ESRD of 3.4 years. The 1-, 5-, and 10-year renal survival from diagnosis were 77%, 48%, and 29% respectively. Renal response was observed only in 5 patients (22%), all of them after achieving hematologic complete response. Median OS from diagnosis was significantly better for those who underwent kidney transplantation versus those who remained on dialysis (19.8 years vs. 8.3 years, P = 0.016). Among patients who underwent kidney transplantation, the shortest survival from MIDD diagnosis was 13.7 years and the longest was 27.8 years. Of the 3 patients with kidney transplants who died, the time from the first kidney transplantation to death was 7.4, 18.8, and 20.4 years. Graft loss due to disease recurrence occurred at 4 months and 3.8 years after kidney transplantation in 2 patients who either were not treated or did not respond to treatment. Conclusion: As treatments for MIDD have dramatically improved, more patients are achieving sustained hematologic responses with longer patient and graft survival after kidney transplantation. Keywords: kidney transplantation, MIDD, monoclonal Ig deposition disease

Casitas B lymphoma (c-Cbl) is an E3 ubiquitin ligase and a negative regulator of colorectal cancer (CRC). Despite its high expression in immune cells, the effect of c-Cbl on the tumor microenvironment remains poorly understood. Here we demonstrate that c-Cbl alters the tumor microenvironment and suppresses Programmed cell death-1 (PD-1) protein, an immune checkpoint receptor. Using syngeneic CRC xenografts, we observed significantly higher growth of xenografts and infiltrating immune cells in c-Cbl+/− compared to c-Cbl+/+ mice. Tumor-associated CD8+ T-lymphocytes and macrophages of c-Cbl+/− mice showed 2–3-fold higher levels of PD-1. Functionally, macrophages from c-Cbl+/− mice showed a 4–5-fold reduction in tumor phagocytosis, which was restored with an anti-PD-1 neutralizing antibody suggesting regulation of PD-1 by c-Cbl. Further mechanistic probing revealed that C-terminus of c-Cbl interacted with the cytoplasmic tail of PD-1. c-Cbl destabilized PD-1 through ubiquitination- proteasomal degradation depending on c-Cbl’s RING finger function. This data demonstrates c-Cbl as an E3 ligase of PD-1 and a regulator of tumor microenvironment, both of which were unrecognized components of its tumor suppressive activity. Advancing immune checkpoint and c-Cbl biology, our study prompts for probing of PD-1 regulation by c-Cbl in conditions driven by immune checkpoint abnormalities such as cancers and autoimmune diseases.

Patients with malignancy are at 4- to 7-fold higher risk of venous thromboembolism (VTE), a potentially fatal, yet preventable complication. Although general mechanisms of thrombosis are enhanced in these patients, malignancy-specific triggers and their therapeutic implication remain poorly understood. Here we examined a colon cancer-specific VTE model and probed a set of metabolites with prothrombotic propensity in the inferior vena cava (IVC) ligation model. Athymic mice injected with human colon adenocarcinoma cells exhibited significantly higher IVC clot weights, a biological readout of venous thrombogenicity, compared with the control mice. Targeted metabolomics analysis of plasma of mice revealed an increase in the blood levels of kynurenine and indoxyl sulfate (tryptophan metabolites) in xenograft-bearing mice, which correlated positively with the increase in the IVC clot size. These metabolites are ligands of aryl hydrocarbon receptor (AHR) signaling. Accordingly, plasma from the xenograft-bearing mice activated the AHR pathway and augmented tissue factor (TF) and plasminogen activator inhibitor 1 (PAI-1) levels in venous endothelial cells in an AHR-dependent manner. Consistent with these findings, the endothelium from the IVC of xenograft-bearing animals revealed nuclear AHR and upregulated TF and PAI-1 expression, telltale signs of an activated AHR-TF/PAI-1 axis. Importantly, pharmacological inhibition of AHR activity suppressed TF and PAI-1 expression in endothelial cells of the IVC and reduced clot weights in both kynurenine-injected and xenograft-bearing mice. Together, these data show dysregulated tryptophan metabolites in a mouse cancer model, and they reveal a novel link between these metabolites and the control of the AHR-TF/PAI-1 axis and VTE in cancer.

Peripheral artery disease (PAD) represents a major health care burden. Despite the advent of screening and interventional procedures, the long-term clinical outcomes remain suboptimal, especially in patients with chronic kidney disease (CKD). While CKD and PAD share common predisposing factors, emerging studies indicate that their co-existence is not merely an association; instead, CKD represents a strong, independent risk factor for PAD. These findings implicate CKD-specific mediators of PAD that remain incompletely understood. Moreover, there is a need to understand the mechanisms underlying poor outcomes after interventions for PAD in CKD. This review discusses unique clinical aspects of PAD in patients with CKD, including high prevalence and worse outcomes after vascular interventions and the influence of renal allograft transplantation. In doing so, it also highlights underappreciated aspects of PAD in patients with CKD, such as disparities in revascularization and higher peri-procedural mortality. While previous reviews have discussed general mechanisms of PAD pathogenesis, focusing on PAD in CKD, this review underscores a need to probe for CKD-specific pathogenic pathways that may unravel novel biomarkers and therapeutic targets in PAD and ultimately improve the risk stratification and management of patients with CKD and PAD.

Kidney transplantation (KT) is the most effective way to decrease the high morbidity and mortality of patients with end-stage renal disease. However, KT does not completely reverse the damage done by years of decreased kidney function and dialysis. Furthermore, new offending agents (in particular, immunosuppression) added in the post-transplant period increase the risk of complications. Cardiovascular (CV) disease, the leading cause of death in KT recipients, warrants pre-transplant screening based on risk factors. Nevertheless, the screening methods currently used have many shortcomings and a perfect screening modality does not exist. Risk factor modification in the pre- and post-transplant periods is of paramount importance to decrease the rate of CV complications post-transplant, either by lifestyle modification (for example, diet, exercise, and smoking cessation) or by pharmacological means (for example, statins, anti-hyperglycemics, and so on). Post-transplantation diabetes mellitus (PTDM) is a major contributor to mortality in this patient population. Although tacrolimus is a major contributor to PTDM development, changes in immunosuppression are limited by the higher risk of rejection with other agents. Immunosuppression has also been implicated in higher risk of malignancy; therefore, proper cancer screening is needed. Cancer immunotherapy is drastically changing the way certain types of cancer are treated in the general population; however, its use post-transplant is limited by the risk of allograft rejection. As expected, higher risk of infections is also encountered in transplant recipients. When caring for KT recipients, special attention is needed in screening methods, preventive measures, and treatment of infection with BK virus and cytomegalovirus. Hepatitis C virus infection is common in transplant candidates and in the deceased donor pool; however, newly developed direct-acting antivirals have been proven safe and effective in the pre- and post-transplant periods. The most important and recent developments on complications following KT are reviewed in this article.

Emerging evidence in animal models of chronic kidney disease (CKD) implicates Aryl Hydrocarbon Receptor (AHR) signaling as a mediator of uremic toxicity. However, details about its tissue-specific and time-dependent activation in response to various renal pathologies remain poorly defined. Here, a comprehensive analysis of AHR induction was conducted in response to discrete models of kidney diseases using a transgenic mouse line expressing the AHR responsive-promoter tethered to a β-galactosidase reporter gene. Following validation using a canonical AHR ligand (a dioxin derivative), the transgenic mice were subjected to adenine-induced and ischemia/reperfusion-induced injury models representing CKD and acute kidney injury (AKI), respectively, in humans. Indoxyl sulfate was artificially increased in mice through the drinking water and by inhibiting its excretion into the urine. Adenine-fed mice showed a distinct and significant increase in β-galactosidase in the proximal and distal renal tubules, cardiac myocytes, hepatocytes, and microvasculature in the cerebral cortex. The pattern of β-galactosidase increase coincided with the changes in serum indoxyl sulfate levels. Machine-learning–based image quantification revealed positive correlations between indoxyl sulfate levels and β-galactosidase expression in various tissues. This pattern of β-galactosidase expression was recapitulated in the indoxyl sulfate–specific model. The ischemia/reperfusion injury model showed increase in β-galactosidase in renal tubules that persisted despite reduction in serum indoxyl sulfate and blood urea nitrogen levels. Thus, our results demonstrate a relationship between AHR activation in various tissues of mice with CKD or AKI and the levels of indoxyl sulfate. This study demonstrates the use of a reporter gene mouse to probe tissue-specific manifestations of uremia in translationally relevant animal models and provide hypothesis-generating insights into the mechanism of uremic toxicity that warrant further investigation.

// Moshe Shashar 1 , Jamaica Siwak 1 , Umit Tapan 2 , Shin Yin Lee 2 , Rosana D. Meyer 3 , Paige Parrack 1 , Josenia Tan 3 , Fatemeh Khatami 1 , Jean Francis 1 , Qing Zhao 3 , Kevan Hartshorn 2 , Vijaya B. Kolachalama 4,5 , Nader Rahimi 3 and Vipul Chitalia 1,4 1 Department of Medicine, Boston University School of Medicine, Boston, MA, USA 2 Department of Medicine, Hematology-Oncology Section, Boston University School of Medicine, Boston, MA, USA 3 Department of Pathology, Boston University School of Medicine, Boston, MA, USA 4 Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA, USA 5 Cardiovascular Division, Brigham and Women’s Hospital, Boston, MA, USA Correspondence to: Vipul Chitalia, email: // Keywords : colorectal cancer, Cbl, Wnt Received : June 16, 2016 Accepted : August 21, 2016 Published : September 20, 2016 Abstract Despite the loss of Adenomatous Polyposis Coli ( APC ) in a majority of colorectal cancers (CRC), not all CRCs bear hallmarks of Wnt activation, such as nuclear β-catenin. This underscores the presence of other Wnt regulators that are important to define, given the pathogenic and prognostic roles of nuclear β-catenin in human CRC. Herein, we investigated the effect of Casitas B-lineage lymphoma (c-Cbl) on nuclear β-catenin, which is an oncoprotein upregulated in CRC due to loss-of-function APC or gain-of-function CTNNB1 mutations. Despite mechanistic rationale and recent discoveries of c-Cbl’s mutations in solid tumors, little is known about its functional importance in CRC. Our study in a cohort of human CRC patients demonstrated an inverse correlation between nuclear β-catenin and c-Cbl. Further investigation showed that the loss of c-Cbl activity significantly enhanced nuclear β-catenin and CRC tumor growth in cell culture and a mouse xenograft model. c-Cbl interacted with and downregulated β-catenin in a manner that was independent of CTNNB1 or APC mutation status. This study demonstrates a previously unrecognized function of c-Cbl as a negative regulator of CRC.

KDIGO recently updated its clinical practice guideline for the prevention, diagnosis, evaluation, and treatment of hepatitis C virus (HCV) infection in patients with chronic kidney disease (CKD). The management of HCV in patients with CKD has dramatically shifted over the past 10 years with the development of direct-acting antiviral (DAA) agents and subsequent demonstration of their efficacy in CKD populations. The opportunity to cure HCV with DAA treatment has impacted all aspects of the KDIGO guideline on HCV in CKD including: (a) HCV diagnosis in CKD populations; (b) HCV treatment in CKD populations; (c) preventing HCV transmission in HD units; (d) management of HCV before and after kidney transplantation; and (e) management of HCV-associated glomerular disease. This review summarizes and discusses the major recommendations, along with the implication of the guideline on clinical practice.

Hepatitis C virus (HCV) infection is prevalent in patients with kidney disease including transplant candidates and recipients. It is associated with increased morbidity and mortality in end-stage renal disease patients and also increases the risk of allograft rejection and decreases allograft and patient survival post-transplant. Newly developed direct acting antivirals have revolutionized the way HCV is treated. Whether patients are treated before or after kidney transplantation, the cure rates with direct acting antivirals are90%. Great debate has formed revolving the optimal timing to treat kidney transplant candidates. On the one hand, treatment before transplantation decreases early post-transplant complications related to HCV. On the other, postponing treatment until after transplantation opens the possibility of transplanting a kidney from a HCV positive donor, which is associated with shorter waiting time and improved organ utilization by expanding the organ donor pool. Most patients living in an area where waiting time is reduced by accepting an HCV positive kidney would benefit by the strategy of treatment post-transplantation, but this decision needs to be individualized in a patient-by-patient basis given that there are special circumstances (i.e., severe HCV-related extrahepatic manifestations, availability of live donors, etc.) in which treatment before transplant might be preferred.

Glomerulopathy due to dysproteinemia can have a wide spectrum of pathologic and clinical features based on specific characteristics of the abnormal protein and the response induced within the parenchymal tissue. Monoclonal immunoglobulin G (IgG) deposition can manifest as a different glomerular disease. Proliferative glomerulonephritis (GN) with monoclonal IgG deposits (PGNMID) is a unique entity mimicking immune complex GN that does not conform to any of those subtypes. IgG monoclonal granular deposition in the glomeruli with a pattern similar to immune complex disease suggested by C3 and C1q deposition should prompt consideration of PGNMID. Literature is scarce in terms of recurrence of disease in renal allografts. In this article we present the clinical-pathologic features of three cases of PGNMID in the renal allograft showing the variable course and manifestation of the disease.

Focal segmental glomerulosclerosis (FSGS) is a leading cause of end-stage renal disease and has a high recurrence rate after kidney transplantation, attributed to a circulating permeability factor. Plasmapheresis is the treatment of choice after recurrence to remove the circulating factor. We present a case of recurrent FSGS 6 years after transplantation. It is instructive because proteinuria did not respond to intensive plasmapheresis—combined with rituximab—until the possibility of ineffective apheresis secondary to multiple aneurysms in the arteriovenous fistula (AVF) was considered. Proteinuria improved soon after alternative access for plasmapheresis was secured and AVF aneurysms were surgically repaired.

Chronic kidney disease (CKD/uremia) remains vexing because it increases the risk of atherothrombosis and is also associated with bleeding complications on standard antithrombotic/antiplatelet therapies. Although the associations of indolic uremic solutes and vascular wall proteins [such as tissue factor (TF) and aryl hydrocarbon receptor (AHR)] are being defined, the specific mechanisms that drive the thrombotic and bleeding risks are not fully understood. We now present an indolic solute-specific animal model, which focuses on solute-protein interactions and shows that indolic solutes mediate the hyperthrombotic phenotype across all CKD stages in an AHR- and TF-dependent manner. We further demonstrate that AHR regulates TF through STIP1 homology and U-box-containing protein 1 (STUB1). As a ubiquitin ligase, STUB1 dynamically interacts with and degrades TF through ubiquitination in the uremic milieu. TF regulation by STUB1 is supported in humans by an inverse relationship of STUB1 and TF expression and reduced STUB1-TF interaction in uremic vessels. Genetic or pharmacological manipulation of STUB1 in vascular smooth muscle cells inhibited thrombosis in flow loops. STUB1 perturbations reverted the uremic hyperthrombotic phenotype without prolonging the bleeding time, in contrast to heparin, the standard-of-care antithrombotic in CKD patients. Our work refines the thrombosis axis (STUB1 is a mediator of indolic solute-AHR-TF axis) and expands the understanding of the interconnected relationships driving the fragile thrombotic state in CKD. It also establishes a means of minimizing the uremic hyperthrombotic phenotype without altering the hemostatic balance, a long-sought-after combination in CKD patients., National Institutes of Health (U.S.) (Grant R01HL132325), National Institutes of Health (U.S.) (Grant R01CA175382), National Institute of General Medical Sciences (U.S.) (Grant R01GM49039), American Heart Association (Grant 12FTF12080241)

Background While racial disparity in colorectal cancer survival have previously been studied, whether this disparity exists in patients with metastatic colorectal cancer receiving care at safety net hospitals (and therefore of similar socioeconomic status) is poorly understood. Methods We examined racial differences in survival in a cohort of patients with stage IV colorectal cancer treated at the largest safety net hospital in the New England region, which serves a population with a majority (65%) of non-Caucasian patients. Data was extracted from the hospital’s electronic medical record. Survival differences among different racial and ethnic groups were examined graphically using Kaplan-Meier analysis. A univariate cox proportional hazards model and a multivariable adjusted model were generated. Results Black patients had significantly lower overall survival compared to White patients, with median overall survival of 1.9 years and 2.5 years respectively. In a multivariate analysis, Black race posed a significant hazard (HR 1.70, CI 1.01–2.90, p = 0.0467) for death. Though response to therapy emerged as a strong predictor of survival (HR = 0.4, CI = 0.2-0.7, p = 0.0021), it was comparable between Blacks and Whites. Conclusions Despite presumed equal access to healthcare and socioeconomic status within a safety-net hospital system, our results reinforce findings from previous studies showing lower colorectal cancer survival in Black patients, and also point to the importance of investigating other factors such as genetic and pathologic differences.

Thrombotic microangiopathy (TMA) is characterized by the presence of microangiopathic hemolytic anemia and thrombocytopenia along with organ dysfunction, and pathologically, by the presence of microthrombi in multiple microvascular beds. Delays in diagnosis and initiation of therapy are common due to the low incidence, variable presentation, and poor awareness of these diseases, underscoring the need for interdisciplinary approaches to clinical care for TMA. We describe a new approach to improve clinical management via a TMA team that originally stemmed from an Affinity Research Collaborative team focused on thrombosis and hemostasis. The TMA team consists of clinical faculty from different disciplines who together are charged with the responsibility to quickly analyze clinical presentations, guide laboratory testing, and streamline prompt institution of treatment. The TMA team also includes faculty members from a broad range of disciplines collaborating to elucidate the pathogenesis of TMA. To this end, a clinical database and biorepository have been constructed. TMA leaders educate front-line providers from other departments through presentations in various forums across multiple specialties. Facilitated by an Affinity Research Collaborative mechanism, we describe an interdisciplinary team dedicated to improving both clinical care and translational research in TMA.

Chronic kidney disease (CKD) is characterized by retention of a number of toxins, which unleash cellular damage. CKD environment with these toxins and a host of metabolic abnormalities (collectively termed as uremic milieu) is highly thrombogenic. CKD represents a strong and independent risk factor for both spontaneous venous and arterial (post-vascular injury) thrombosis. Emerging evidence points to a previously unrecognized role of some of the pro-thrombotic uremic toxins. Here we provide an overview of thrombosis in CKD and an update on indolic uremic toxins, which robustly increase tissue factor, a potent pro-coagulant, in several vascular cell-types enhancing thrombosis. This panel of uremic toxins, which we term ‘thrombolome’ (thrombosis and metabolome), represents a novel risk factor for thrombosis and can be further explored as biomarkers for post-vascular interventional thrombosis in patients with CKD.

Hypomagnesemia is associated with increased peripheral insulin resistance in the general population. It is frequently seen after renal transplantation. We examined its role as a risk factor for new-onset diabetes after transplantation (NODAT) and new-onset pre-diabetes after transplantation (NOPDAT). A retrospective analysis of 138 previously non-diabetic renal transplant recipients was conducted. Cox and logistic regression analyses were performed to examine the associations between 1-month post-transplant serum magnesium level and subsequent diagnoses of NODAT/NOPDAT. NODAT was diagnosed in 34 (24.6 %) and NOPDAT in 12 (8.7 %) patients. Median time to diagnosis of NODAT/NOPDAT was 20.4 months (interquartile range [IQR] 6.8–34.8). Median follow up for the entire group was 3.5 years (IQR 2.3–5.6). Mean magnesium level at 1 month after transplantation was significantly lower in patients subsequently diagnosed with NODAT/NOPDAT (1.60 ± 0.27 vs. 1.76 ± 0.29 mg/dl, p = 0.002). Cox regression analysis identified a trend towards developing NODAT/NOPDAT with lower baseline magnesium levels (hazard ratio 0.89 per 0.1 mg/dl increment in magnesium level, 95 % confidence interval [CI] = 0.78–1.01, p = 0.07); a stronger relationship between the two variables was seen at logistic regression analysis (odds ratio 0.81 per 0.1 mg/dl increment in serum magnesium (95 % CI 0.67–0.98, p = 0.03). A lower magnesium level at 1 month after transplantation may be predictive of a subsequent diagnosis of glucose intolerance or diabetes in renal transplant recipients. Whether replenishing magnesium stores can prevent development of these disorders requires further investigation.

Strongyloides stercoralis hyperinfection in an immunocompromised host has a high mortality rate but may initially present with non-specific pulmonary and gastrointestinal symptoms. Donor-derived S. stercoralis by kidney transplantation is an uncommon diagnosis and difficult to prove. We report two renal allograft recipients on different immunosuppressive maintenance regimens that developed strongyloidiasis after transplantation from the same donor. Recipient 1 presented with a small bowel obstruction. Larvae were demonstrated on a duodenal biopsy and isolated from gastric, pulmonary, and stool samples. Serologic testing for S. stercoralis was negative at a referral laboratory but positive at the Centers for Disease Control. The patient's hospital course was complicated by a hyperinfection syndrome requiring subcutaneous ivermectin due to malabsorption. Recipient 1 survived but the allograft failed. Recipient 2 had larvae detected in stool samples after complaints of diarrhea and was treated. On retrospective testing for S. stercoralis, pre-transplant serum collected from the donor and Recipient 1 was positive and negative, respectively. Donor-derived strongyloidiasis by renal transplantation is a preventable disease that may be affected by the immunosuppressive maintenance regimen. Subcutaneous ivermectin is an option in the setting of malabsorption. Finally, routine screening for S. stercoralis infection in donors from endemic areas may prevent future complications.

Mineral and bone disorders that precede kidney transplantation are exacerbated in the post-transplant setting by tertiary hyperparathyroidism and immunosuppressive regimens. Bone mineral density (BMD) decreases following transplantation, leading to increased fracture risk. The effect of bisphosphonates on fracture is unknown. The aim of this study was to update estimates of change in BMD and fracture rates in bisphosphonate-treated kidney transplant recipients through meta-analysis. Studies comparing bisphosphonate therapy to standard of care were included if follow-up duration was more than 6 months. We performed random-effects meta-analysis to determine the effect of bisphosphonates on lumbar spine and femoral neck BMD and fracture rates. Bisphosphonates improved femoral neck and lumbar spine BMD compared with controls (0.055 g/cm(2) , 95% CI 0.012-0.099 and 0.053 g/cm(2) , 95% CI 0.032-0.074, respectively) without adversely affecting serum creatinine or calcium. This corresponded to an unweighted improvement in BMD of 6.0% and 7.4%, respectively. There was no difference in fracture incidence in the two groups. Bisphosphonate therapy in kidney transplant recipients is associated with a statistically significant improvement in BMD at the lumbar spine and femoral neck. There was no difference in fracture incidence. Bisphosphonates did not adversely affect allograft dysfunction or serum calcium levels.

Background Hyperparathyroidism is present in up to 50% of transplant recipients 1 year after transplant, often despite good graft function. Posttransplant patients frequently have hypercalcemia-associated hyperparathyroidism, limiting the role of vitamin D analogues and sometimes requiring parathyroidectomy. Multiple observational studies have investigated treatment of posttransplant hyperparathyroidism with the calcimimetic agent cinacalcet. Methods We performed a systematic review and meta-analysis of prospective and retrospective studies from 2004 through January 26, 2012, using MEDLINE. We identified studies evaluating treatment with cinacalcet in renal transplant recipients with hyperparathyroidism. We performed random effects meta-analysis to determine changes in calcium, phosphorus, parathyroid hormone, and serum creatinine. Results Twenty-one studies with 411 kidney transplant recipients treated with cinacalcet for hyperparathyroidism met inclusion criteria. Patients were treated for 3 to 24 months. By meta-analysis, calcium decreased by 1.14 mg/dL (95% confidence interval, -1.00 to -1.28), phosphorus increased by 0.46 mg/dL (95% confidence interval, 0.28-0.64), parathyroid hormone decreased by 102 pg/mL (95% confidence interval, -69 to -134), and there was no significant change in creatinine (0.02 mg/dL decrease; 95% confidence interval, -0.09 to 0.06). Cinacalcet resulted in hypocalcemia in seven patients. The most common side effect was gastrointestinal intolerance. Conclusions From nonrandomized studies, cinacalcet appears to be safe and effective for the treatment of posttransplant hyperparathyroidism. Larger observational studies and randomized controlled trials, performed over longer follow-up times and looking at clinical outcomes, are needed to corroborate these findings.

INTRODUCTION BK polyomavirus (BKPyV) continues to impact renal transplant recipients (RTR). The New England BK Consortium aims to jointly optimize screening and management of BKPyV. METHODS Our first project was to survey centers' BKPyV screening protocols and compare them to consensus guidelines. RESULTS Thirteen of 15 centers (86.7%) returned the survey. Only two center reported using monitoring parameters that were in line with consensus guidelines for BKPyV screening, while the majority of centers reported less intensive methods and shorter duration. One center reported performing renal biopsies in all patients with plasma viral loads >10 000 copies/mL, while all other centers only perform for-cause biopsies. For presumptive nephropathy, 11 centers recommend a biopsy for confirmation. For management of documented BKPyV-associated nephropathy, 12 centers propose further immunosuppression reduction. Nine centers report CNI dose reduction as their primary treatment. More than half of centers surveyed reported use of leflunomide, cidofovir or intravenous immunoglobulin. CONCLUSIONS There was a large variance in BKPyV screening and management strategies among centers. Due to these results, all participating centers agreed to implement uniform screening and aim to optimize management protocols.

Lessons from an animal model that faithfully resembles human membranous nephropathy (MN) have informed our understanding of the pathogenesis of this organ-specific autoimmune disease and common cause of the nephrotic syndrome. Once it was established that the subepithelial immune deposits that characterize experimental MN form in situ when circulating antibodies bind to an intrinsic podocyte antigen, it was merely a matter of time before the human antigen was identified. The M-type phospholipase A2 receptor 1 (PLA2R) represents the major target antigen in primary MN, and thrombospondin type 1 domain-containing 7A (THSD7A) was more recently identified as a minor antigen. Serological tests for anti-PLA2R as well as kidney biopsy specimen staining for PLA2R exhibit more than 90% specificity and 70% to 80% sensitivity for the diagnosis of primary MN in most populations. The assays distinguish most cases of primary MN from MN associated with other systemic diseases, and sequential titers of anti-PLA2R are useful to monitor treatment response. A positive pre-transplantation test for anti-PLA2R is also helpful for predicting the risk of post-transplantation recurrence. Identification of target epitopes within PLA2R as well as the genetic association of primary MN with class II major histocompatibility and PLA2R1 variants are 2 additional examples of our evolving understanding of this disease.

Patients with CKD suffer high rates of thrombosis, particularly after endovascular interventions, yet few options are available to improve management and reduce thrombotic risk. We recently demonstrated that indoxyl sulfate (IS) is a potent CKD-specific prothrombotic metabolite that induces tissue factor (TF) in vascular smooth muscle cells (vSMCs), although the precise mechanism and treatment implications remain unclear. Because IS is an agonist of the aryl hydrocarbon receptor (AHR), we first examined the relationship between IS levels and AHR-inducing activity in sera of patients with ESRD. IS levels correlated significantly with both vSMC AHR activity and TF activity. Mechanistically, we demonstrated that IS activates the AHR pathway in primary human aortic vSMCs, and further, that AHR interacts directly with and stabilizes functional TF. Antagonists directly targeting AHR enhanced TF ubiquitination and degradation and suppressed thrombosis in a postinterventional model of CKD and endovascular injury. Furthermore, AHR antagonists inhibited TF in a manner dependent on circulating IS levels. In conclusion, we demonstrated that IS regulates TF stability through AHR signaling and uncovered AHR as an antithrombotic target and AHR antagonists as a novel class of antithrombotics. Together, IS and AHR have potential as uremia-specific biomarkers and targets that may be leveraged as a promising theranostic platform to better manage the elevated thrombosis rates in patients with CKD.

Wnt signaling plays important roles in both the tumor-induced angiogenesis and tumorigenesis through the transcriptionally active nuclear β-catenin. Recently, c-Cbl was identified as a unique E3 ubiquitin ligase targeting the active nuclear β-catenin. However, little is known about the molecular mechanisms by which c-Cbl regulates ubiquitination and degradation of active β-catenin. Here, we demonstrate that Wnt activation promotes the phosphorylation of c-Cbl at tyrosine 731(Tyr-731), which increases c-Cbl dimerization and binding to β-catenin. Tyr-731 phosphorylation and dimerization mediate c-Cbl nuclear translocation and lead to the degradation of nuclearly active β-catenin in the Wnt-on phase. c-Cbl activation also inhibits expression of the pro-angiogenic Wnt targets, IL-8 and VEGF. Phospho-Tyr-731-inactive mutant c-Cbl (Y731F) enhances and phosphomimetic mutant c-Cbl (Y731E) suppresses angiogenesis in zebrafish. Taken together, we have identified a novel mechanism for the regulation of active nuclear β-catenin by c-Cbl and its critical role in angiogenesis. This mechanism can be further explored to modulate both the pathological angiogenesis and the tumorigenesis.

This letter to the editor documents the successful use of acetazolamide in a patient with lithium-induced nephrogenic diabetes insipidus.

Diabetic nephropathy remains the most common cause of ESRD, accounting for more than 40% of patients treated with dialysis. The standard therapy for diabetic nephropathy consists of early detection, aggressive glycemic control, and treatment of hypertension and proteinuria using renin-angiotensin

e15090 Background: Aberrant hyperactive Wnt/ß-catenin signaling is critical in colorectal cancer (CRC) tumorigenesis. Casitas B-lineage Lymphoma (c-Cbl) is a negative regulator of Wnt signaling, and functions as a tumor suppressor. The objective of this study was to evaluate c-Cbl expression as a predictive marker of survival in patients with metastatic CRC (mCRC). Methods: Patients with mCRC treated at Boston University Medical Center between 2004 and 2014 were analyzed. c-Cbl and nuclear ß-catenin expression was quantified in explanted biopsies using a customized color-based image segmentation pipeline. Quantification was normalized to the total tumor area in an image, and deemed ‘low’ or ‘high’ according to the mean normalized values of the cohort. A supervised machine-learning model based on bootstrap aggregating was constructed with c-Cbl expression as the input feature and 3-year survival as output. Results: Of the 72 subjects with mCRC, 52.78% had high and 47.22% had low c-Cbl expression. Patients with high c-Cbl had significantly better median overall survival than those with low c-Cbl expression (3.7 years vs. 1.8 years; p = 0.0026), and experienced superior 3-year survival (47.37% vs 20.59%; p = 0.017). Intriguingly, nuclear ß-catenin expression did not correlate with survival. No significant differences were detected between high and low c-Cbl groups in baseline characteristics (demographics, comorbidities), tumor-related parameters (primary tumor location, number of metastasis, molecular features) or therapy received (surgery, chemotherapy regimen). A 5-fold cross-validated machine-learning model associated with 3-year survival demonstrated an area under the curve of 0.729, supporting c-Cbl expression as a predictor of mCRC survival. Conclusions: Our results show that c-Cbl expression is associated with and predicts mCRC survival. Demonstration of these findings despite the small cohort size underscores the power of quantitative histology and machine-learning application. While further work is needed to validate c-Cbl as a novel biomarker of mCRC survival, this study supports c-Cbl as a regulator of Wnt/ß-catenin signaling and a suppressor of other oncogenes in CRC tumorigenesis.