Time to Abolish Metrics That Sustain Systemic Racism in Kidney Allocation.

This Viewpoint discusses how the Kidney Donor Profile Index (KDPI) in its current form is not fit to guide kidney allocation because it devalues organ donation by Black donors based on a weak association between donor race and kidney transplant failure.

The Tabula Sapiens: A multiple-organ, single-cell transcriptomic atlas of humans.

Molecular characterization of cell types using single-cell transcriptome sequencing is revolutionizing cell biology and enabling new insights into the physiology of human organs. We created a human reference atlas comprising nearly 500,000 cells from 24 different tissues and organs, many from the same donor. This atlas enabled molecular characterization of more than 400 cell types, their distribution across tissues, and tissue-specific variation in gene expression. Using multiple tissues from a single donor enabled identification of the clonal distribution of T cells between tissues, identification of the tissue-specific mutation rate in B cells, and analysis of the cell cycle state and proliferative potential of shared cell types across tissues. Cell type-specific RNA splicing was discovered and analyzed across tissues within an individual.

Ciliated hepatic foregut cysts in children.

Ciliated hepatic foregut cyst (CHFC) is a rare foregut developmental malformation usually diagnosed in adulthood; however, rare cases have been reported in the pediatric population. CHFC can transform into a squamous cell carcinoma resulting in death despite surgical resection of the isolated malignancy. We report the presentation, evaluation, and surgical management of a symptomatic 17-year-old girl found to have a 6.5 x 4.5 cm CHFC and suggest that all patients with suspected CHFC undergo prompt evaluation and complete cyst excision.

Fulminant hepatic failure from primary hepatic lymphoma: successful treatment with orthotopic liver transplantation and chemotherapy.

Systemic lymphomas may involve the liver but rarely cause fulminant hepatic failure (FHF). Acute liver failure from primary hepatic lymphoma (PHL) is even less common with most patients succumbing to the sequelae of FHF before the correct diagnosis is made. We report a patient who underwent successful orthotopic liver transplant (OLT) and chemotherapy for FHF secondary to PHL. This previously-well male developed profound coagulopathy and encephalopathy 6 weeks after the onset of jaundice and fatigue. Workup failed to reveal the underlying cause of his liver failure and the patient soon required urgent OLT. Pathologic evaluation of his explanted liver revealed a malignant T-cell rich, large B-cell non-Hodgkin's lymphoma with widespread hepatocellular necrosis. The patient made an excellent clinical recovery and is undergoing CHOP-Rituxan chemotherapy. This scenario demonstrates that lymphoma should be considered in the differential diagnosis of FHF without clear etiology because of the potential for intervention with transplant and chemotherapy.

Vascular access in hemodialysis: issues, management, and emerging concepts.

This article (1) identifies the types of hemodialysis access, (2) summarizes the clinical standard of care for dialysis access grafts and fistulae, (3) describes the pathology and pathogenesis of venous stenosis in dialysis access grafts and fistulae, (4) tabulates avail-able therapies for hemodialysis vascular access dysfunction and speculates on the rea-sons for the lack of effective therapies, and (5) discusses the development and application of novel therapeutic interventions for this difficult clinical problem. The possibility that dialysis access grafts and fistulae could be the ideal clinical model for testing novel local therapies to block neointimal hyperplasia is discussed.

External beam radiation attenuates venous neointimal hyperplasia in a pig model of arteriovenous polytetrafluoroethylene (PTFE) graft stenosis.

PURPOSE: Hemodialysis vascular access dysfunction is an enormous clinical problem that causes great morbidity and costs well over one billion dollars per annum. The vast majority of hemodialysis vascular access dysfunction occurs as a result of venous stenosis and thrombosis at the graft-vein anastomosis. At a cellular level, this venous stenosis is the result of venous neointimal hyperplasia (VNH). There are, unfortunately, no effective therapies for VNH. The purpose of this study was to assess the role of external radiation therapy in preventing VNH and venous stenosis. METHODS AND MATERIALS: Seven-centimeter polytetrafluoroethylene loop grafts were placed bilaterally between the femoral artery and vein of 12 Yorkshire Cross pigs. One side was treated with a single 16-Gy dose of external beam radiation with a linear accelerator, while the contralateral side served as an internal control. Swine were killed after 28 days, and the grafts were carefully dissected out and removed. Neointimal hyperplasia and luminal stenosis were then assessed morphometrically at the graft-vessel anastomoses. RESULTS: External beam radiation therapy significantly reduced the amount of luminal stenosis at the graft-vein anastomosis, with minimal local and systemic toxicity. CONCLUSIONS: External beam radiation therapy could be a useful and clinically relevant local treatment for venous stenosis in polytetrafluoroethylene dialysis grafts.

External beam radiation therapy for PTFE dialysis grafts: a pilot study.

PURPOSE: The aim of this study was to identify the effects of external beam radiation on PTFE dialysis graft dysfunction. METHODS: Seven patients who underwent PTFE dialysis graft angioplasty were randomized to receive either two 8 Gy doses of external beam radiation or no radiation. The primary endpoint was time to graft thrombosis with a secondary endpoint of time to first intervention. RESULTS: There was no statistically significant difference between the two groups in either of the endpoints, although grafts in the radiation group had a shorter time to thrombosis or intervention. CONCLUSIONS: Our results demonstrate technical feasibility for use of external beam radiation in the setting of dialysis vascular access graft dysfunction. Larger randomized studies are required to identify whether there is a clinical benefit from this intervention.

Development of a local perivascular paclitaxel delivery system for hemodialysis vascular access dysfunction: polymer preparation and in vitro activity.

Hemodialysis vascular access dysfunction (HVAD) is currently a huge clinical problem. The major cause of HVAD is venous stenosis (as a result of venous neointimal hyperplasia) which leads to thrombosis in polytetrafluoroethylene dialysis access grafts and fistulae. Despite the magnitude of the clinical problem there are currently no effective therapeutic interventions for this condition. In an attempt to reduce the morbidity associated with HVAD, we have developed and validated a local perivascular paclitaxel release system for use in a pig model of arteriovenous graft stenosis. Ethylene vinyl acetate polymers with 5% paclitaxel were formulated. The release profile of paclitaxel was then manipulated to maximize its biological impact in the in vivo situation. In vitro experiments were performed to confirm that the paclitaxel released from the polymer was biologically active against cell types that were similar to those present in the in vivo lesion of neointimal hyperplasia. Our results demonstrate that the paclitaxel polymer wraps which we have developed are mechanically stable with a burst release phase followed by a slower continuous release phase. The paclitaxel released from these polymeric wraps retains its physicochemical and biological properties and is able to inhibit the proliferation of smooth muscle cells, endothelial cells and fibroblasts in vitro. We believe that these paclitaxel-loaded polymeric wraps could be ideally suited for perivascular drug delivery in the context of dialysis access grafts and fistulae.

Perivascular paclitaxel wraps block arteriovenous graft stenosis in a pig model.

BACKGROUND: Haemodialysis vascular access dysfunction is currently a huge clinical problem. In an attempt to reduce the morbidity associated with haemodialysis vascular access dysfunction, we have previously developed and validated a local perivascular paclitaxel release system that has been shown to release paclitaxel for at least 3 weeks. The aim of the current study was to evaluate the in vivo use of these perivascular wraps (for both safety and efficacy) at different time points in our pig model of arteriovenous graft stenosis. METHODS: Paclitaxel-loaded ethylene vinyl acetate wraps were placed around the graft-vein anastomosis on one side, with control polymers being placed on the contralateral side in our pig model of arteriovenous graft stenosis. Animals were sacrificed at early (10-11 days), middle (23-24 days) and late (32-38 days) time points. The entire graft-vein anastomosis was removed at the time of sacrifice and assessed for the extent of luminal stenosis using histomorphometric techniques. RESULT: Graft-vein anastomoses treated with the paclitaxel-loaded polymers had an almost complete absence of luminal stenosis at the middle (23-24 days) and late (32-38 days) time points (when one would expect the development of neointimal hyperplasia) as compared with the contralateral control graft-vein anastomoses (37.90% luminal stenosis in the controls vs 0.10% in the paclitaxel group). There were minimal local side effects from this procedure. CONCLUSIONS: Our results demonstrate the safety and efficacy of paclitaxel-loaded perivascular wraps in the setting of a pig model of arteriovenous graft stenosis. We believe that such a local approach which could be easily applied at the time of surgery is ideally suited for use in the clinical setting of haemodialysis vascular access dysfunction. It is likely that this novel approach could result in a significant reduction in the huge economic and health morbidity costs currently associated with this recalcitrant clinical problem.

Novel therapies for hemodialysis vascular access dysfunction: fact or fiction!

Hemodialysis vascular access dysfunction is a major cause of morbidity in the hemodialysis population and contributes significantly to the overall cost of end-stage renal disease programs. At a histological level, most hemodialysis vascular access dysfunction (in both native arteriovenous fistulae and PTFE dialysis access grafts) is due to venous stenosis and thrombosis, secondary to venous neointimal hyperplasia. However, despite a wealth of experimental and clinical data on the use of novel therapeutic interventions that target neointimal hyperplasia in the setting of coronary artery disease, there are unfortunately no effective therapeutic interventions for hemodialysis vascular access dysfunction at the present time. This is particularly unfortunate, since neointimal hyperplasia in the setting of hemodialysis vascular access fistulae and grafts could be the ideal clinical model to test novel therapeutic interventions for neointimal hyperplasia.

Hemodialysis vascular access dysfunction: from pathophysiology to novel therapies.

Hemodialysis vascular access dysfunction is a major cause of morbidity and hospitalization in the hemodialysis population at a cost of over USD 1 billion per annum. Most hemodialysis grafts fail due to a venous stenosis (venous neointimal hyperplasia) which then results in thrombosis of the graft. Despite the magnitude of the clinical problem there are currently no effective therapies for this condition. The current review (a) describes the pathogenesis and pathology of venous stenosis in dialysis access grafts and (b) discusses the development and application of novel therapeutic interventions for this difficult clinical problem. Special emphasis is laid on the fact that PTFE dialysis access grafts could be the ideal clinical model for testing out novel local therapies to block neointimal hyperplasia.

Hemodialysis vascular access dysfunction from basic biology to clinical intervention.

Hemodialysis vascular access dysfunction is a major cause of morbidity and hospitalization in the hemodialysis population at a cost of over 1 billion dollars per annum. Venous stenosis and thrombosis as a result of venous neointimal hyperplasia are the major causes of hemodialysis vascular access dysfunction. Despite the magnitude of the clinical problem, there are currently no effective therapies for this condition. We believe that this could be because of an inadequate understanding of the pathogenesis of this condition. At a histological level, venous neointimal hyperplasia (both in human specimens and in a pig model) is characterized by the presence of smooth muscle cells/myofibroblasts, microvessel formation (angiogenesis), and the accumulation of extracellular matrix components, all of which could be potential targets for therapeutic intervention. In particular, polytetrafluoroethylene dialysis access grafts could be the ideal clinical model for testing out novel local therapies to block neointimal hyperplasia. The current review describes the lesion of venous neointimal hyperplasia in human samples and in a pig model and suggests possible future directions for the development of effective local therapies for this condition.

Aggressive venous neointimal hyperplasia in a pig model of arteriovenous graft stenosis.

BACKGROUND: Vascular access dysfunction is the most important cause of morbidity and hospitalization in the hemodialysis population in the United States at a cost of well over one billion dollars per annum. Venous neointimal hyperplasia characterized by stenosis and subsequent thrombosis, is the major cause of polytetrafluoroethylene (PTFE) dialysis graft failure. Despite the magnitude of the problem, there are currently no effective therapies for the prevention or treatment of venous neointimal hyperplasia in PTFE dialysis grafts. We believe that this is partly due to the lack of a validated large animal model of arteriovenous stenosis that could be used to test out novel interventions. METHODS: Seven-centimeter PTFE loop grafts were placed between the femoral artery and vein of domestic pigs. The grafts were removed at 2, 4, 7, 14 and 28 days after surgery and subjected to a detailed histological and immunohistochemical examination. RESULTS: Significant neointimal hyperplasia and venous stenosis developed by 28 days at the graft-vein anastomosis. There was minimal neointimal hyperplasia at the graft-artery anastomosis. Venous neointimal hyperplasia (VNH) was characterized by (a) the presence of smooth muscle cells/myofibroblasts; (b) angiogenesis within both the neointima and adventitia; and (c) the presence of an active macrophage cell layer lining the PTFE graft material. These results are very similar to the human lesion previously described by us in dialysis patients. CONCLUSIONS: We have developed and validated a pig model of venous neointimal hyperplasia that is very similar to the human lesion. We believe that this is an ideal model in which to test out novel interventions for the prevention and treatment of clinical hemodialysis vascular access dysfunction.