Jean Francis

The Aryl Hydrocarbon Receptor is a Critical Regulator of Tissue Factor Stability and an Antithrombotic Target in Uremia

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.

Cinacalcet for the treatment of hyperparathyroidism in kidney transplant recipients: a systematic review and meta-analysis.

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.

Thrombosis in the Uremic Milieu—Emerging Role of “Thrombolome”

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 (postvascular injury) thrombosis. Emerging evidence points to a previously unrecognized role of some of the prothrombotic 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 procoagulant, 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 biomarker for postvascular interventional thrombosis in patients with CKD.

Evaluation of Native Kidney Recovery After Simultaneous Liver-Kidney Transplantation

Background. Debate continues about which liver transplantation candidates with impaired renal function should undergo liver transplant alone versus simultaneous liver-kidney transplantation (SLK). Identifying predictors of native kidney function recovery after SLK requires an accurate measure of the relative function of all three kidneys in patients with SLK. Methods. The distance of a transplanted kidney from the renal scan camera can be substantially different from that of native kidneys. We developed a technique to correct attenuation of counts of all three kidneys based on their depth. Results. In our series of 13 SLK recipients, attenuation correction increased the measured renal function of native kidneys by up to 40%, demonstrating the importance of this procedure for accurately measuring kidney function. Eight patients met the United Network for Organ Sharing (UNOS)-proposed criteria for receiving a SLK, but four of these still had significant native kidney function (>40% of total function) after transplant. Five patients did not meet the UNOS-proposed criteria for SLK, yet only one of these had native kidney function recovery. Conclusion. The criteria proposed by UNOS to determine that SLK is indicated, and thus that native kidney recovery is not expected, are not always accurate. Further study of factors associated with native kidney recovery after SLK is required.

Pyridoxamine, Advanced Glycation Inhibition, and Diabetic Nephropathy

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

The c-Cbl Ubiquitin Ligase Regulates Nuclear β-Catenin and Angiogenesis by Its Tyrosine Phosphorylation Mediated through the Wnt Signaling Pathway

Background: β-Catenin is an important mediator of angiogenesis; however, its molecular regulation is poorly understood. Results: Wnt promotes phosphorylation of c-Cbl on Tyr-731, enhancing its dimerization and nuclear translocation to degrade nuclear β-catenin. Conclusion: Wnt-mediated c-Cbl phosphorylation regulates nuclear β-catenin. Significance: Targeting c-Cbl E3 ligase activity could destabilize β-catenin and inhibit pathological angiogenesis. 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.

Targeting STUB1–tissue factor axis normalizes hyperthrombotic uremic phenotype without increasing bleeding risk

Targeting mediators of the uremic thrombosis axis reverts the uremic hyperthrombotic phenotype without altering the bleeding risk. Striking a balance for anticoagulation Patients with chronic kidney disease can present a therapeutic conundrum because they are not only at increased risk of blood vessel thrombosis but also more likely to experience bleeding complications when treated with anticoagulants. Shashar et al. examined the mechanism of thrombosis in mouse models of renal disease and found a potential therapeutic target in a protein called STUB1. STUB1 is a ubiquitin ligase that interacts with tissue factor, a vascular wall protein that triggers the coagulation signaling cascade. The authors demonstrated that increase in STUB1 can prevent thrombosis but does not prolong bleeding in mouse models of kidney disease, suggesting that this may be a viable approach to antithrombotic management of patients. 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.

c-Cbl mediates the degradation of tumorigenic nuclear β-catenin contributing to the heterogeneity in Wnt activity in colorectal tumors

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-Cbls 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.

Proliferative glomerulonephritis with monoclonal immunoglobulin in renal allografts

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.

Hepatitis C Treatment in Dialysis Patients: Is a New Dawn Approaching?

Address correspondence to Craig E. Gordon, MD, MS, Boston University Medical Center, Department of Nephrology, 650 Albany St, 5th Fl, Boston, MA 02118. E-mail: craig.gordon@bmc. org 2014 by the National Kidney Foundation, Inc. 0272-6386/