Boris Nikolic

Circulating urokinase receptor as a cause of focal segmental glomerulosclerosis

Focal segmental glomerulosclerosis (FSGS) is a cause of proteinuric kidney disease, compromising both native and transplanted kidneys. Treatment is limited because of a complex pathogenesis, including unknown serum factors. Here we report that serum soluble urokinase receptor (suPAR) is elevated in two-thirds of subjects with primary FSGS, but not in people with other glomerular diseases. We further find that a higher concentration of suPAR before transplantation underlies an increased risk for recurrence of FSGS after transplantation. Using three mouse models, we explore the effects of suPAR on kidney function and morphology. We show that circulating suPAR activates podocyte β3 integrin in both native and grafted kidneys, causing foot process effacement, proteinuria and FSGS-like glomerulopathy. Our findings suggest that the renal disease only develops when suPAR sufficiently activates podocyte β3 integrin. Thus, the disease can be abrogated by lowering serum suPAR concentrations through plasmapheresis, or by interfering with the suPAR–β3 integrin interaction through antibodies and small molecules targeting either uPAR or β3 integrin. Our study identifies serum suPAR as a circulating factor that may cause FSGS.

Consensus guidelines for periprocedural management of coagulation status and hemostasis risk in percutaneous image-guided interventions.

From the Division of Vascular and Interventional Radiology, Jefferson Radiology, Hartford Hospital, 85 Seymour St, Ste 200, Hartford, CT 06106 (P.C.M.); Department of Radiology, Boston Healthcare System, VAMC Boston, Massachusetts (C.J.G.); Department of Medical Imaging, Scarborough General Hospital, Richmond Hill, Ontario, Canada (S.K.); Department of Radiology, GI/GU Division, Massachusetts General Hospital, Boston, Massachusetts (D.A.G.); Department of Radiology and Radiologic Sciences, Uniformed Services University of the Health Sciences and Department of Radiology, National Naval Medical Center, Bethesda, Maryland (D.L.M.); RADIA, Everett, Washington (R.B.O.); Department of Radiology, University of Florida, Gainesville, Florida (D.W.P.); Department of Medical Imaging, Division of Vascular and Interventional Radiology, University of Toronto, University Health Network, Toronto, Ontario, Canada (D.K.R.); Department of Interventional Radiology, The Reading Hospital and Medical Center, West Reading, Pennsylvania (D.S.); Radiology Associates of Central Florida, Mt Dora, Florida (M.S.S.); Mallinckrodt Institute of Radiology, St Louis, Missouri (D.A.Z.); and Geisinger System Radiology, Geisinger Health System, Danville, Pennsylvania (J.F.C.). Received November 18, 2008; accepted November 24, 2008. Address correspondence to P.C.M.; E-mail: pmalloy@ jeffersonradiology.com

Modification of kidney barrier function by the urokinase receptor

Podocyte dysfunction, represented by foot process effacement and proteinuria, is often the starting point for progressive kidney disease. Therapies aimed at the cellular level of the disease are currently not available. Here we show that induction of urokinase receptor (uPAR) signaling in podocytes leads to foot process effacement and urinary protein loss via a mechanism that includes lipid-dependent activation of αvβ3 integrin. Mice lacking uPAR (Plaur−/−) are protected from lipopolysaccharide (LPS)-mediated proteinuria but develop disease after expression of a constitutively active β3 integrin. Gene transfer studies reveal a prerequisite for uPAR expression in podocytes, but not in endothelial cells, for the development of LPS-mediated proteinuria. Mechanistically, uPAR is required to activate αvβ3 integrin in podocytes, promoting cell motility and activation of the small GTPases Cdc42 and Rac1. Blockade of αvβ3 integrin reduces podocyte motility in vitro and lowers proteinuria in mice. Our findings show a physiological role for uPAR signaling in the regulation of kidney permeability.

Image-guided Tumor Ablation: Standardization of Terminology and Reporting Criteria—A 10-Year Update

Image-guided tumor ablation has become a well-established hallmark of local cancer therapy. The breadth of options available in this growing field increases the need for standardization of terminology and reporting criteria to facilitate effective communication of ideas and appropriate comparison among treatments that use different technologies, such as chemical (eg, ethanol or acetic acid) ablation, thermal therapies (eg, radiofrequency, laser, microwave, focused ultrasound, and cryoablation) and newer ablative modalities such as irreversible electroporation. This updated consensus document provides a framework that will facilitate the clearest communication among investigators regarding ablative technologies. An appropriate vehicle is proposed for reporting the various aspects of image-guided ablation therapy including classification of therapies, procedure terms, descriptors of imaging guidance, and terminology for imaging and pathologic findings. Methods are addressed for standardizing reporting of technique, follow-up, complications, and clinical results. As noted in the original document from 2003, adherence to the recommendations will improve the precision of communications in this field, leading to more accurate comparison of technologies and results, and ultimately to improved patient outcomes. Online supplemental material is available for this article .

Treatment of severe autoimmune disease by stem-cell transplantation

Transplantation of haematopoietic stem cells — cells capable of self renewing and reconstituting all types of blood cell — can treat numerous lethal diseases, including leukaemias and lymphomas. It may now be applicable for the treatment of severe autoimmune diseases, such as therapy-resistant rheumatoid arthritis and multiple sclerosis. Studies in animal models show that the transfer of haematopoietic stem cells can reverse autoimmunity, and several mechanistic pathways may explain this phenomenon. The outcome of ongoing clinical trials, as well as of studies in patients and animal models, will help to determine the role that stem-cell transplantation can play in the treatment of autoimmune diseases.

Th1 and Th2 mediate acute graft-versus-host disease, each with distinct end-organ targets

STAT4 and STAT6 are transcription factors that play crucial roles in responding to IL-12 and IL-4, respectively. STAT4 gene knockout (STAT4(-/-)) mice have markedly reduced Th1 responses and enhanced Th2 responses. STAT6(-/-) mice show the inverse phenotype. We compared the ability of bone marrow transplantation (BMT) with the inclusion of spleen cells from STAT6(-/-), STAT4(-/-), and wild-type (WT) mice to produce graft-versus-host disease (GVHD) in lethally irradiated MHC-mismatched recipients. Acute GVHD mortality was more rapid when induced by cells from STAT6(-/-) mice than when induced by STAT4(-/-) cells. However, cells from STAT4(-/-) and STAT6(-/-) donors both induced delayed GVHD mortality compared with WT controls, or compared with combined STAT4(-/-) and STAT6(-/-) cells, indicating a contribution of both Th1 cells and Th2 cells to acute GVHD. Recipients of STAT6(-/-) BMT showed evidence of acute GVHD with severe diarrhea and marked weight loss. Recipients of STAT4(-/-) BMT showed signs of GVHD with only initial transient weight loss and later development of severe skin GVHD. Histopathology showed that Th2 responses were required for the induction of both hepatic and severe skin GVHD. In contrast, both Th1 cells and Th2 cells were capable of causing intestinal pathology of GVHD. Our studies demonstrate an additive role for Th1 and Th2 cells in producing acute GVHD, and suggest a cytokine-directed approach to treating end-organ manifestations of GVHD.

Proteolytic processing of dynamin by cytoplasmic cathepsin L is a mechanism for proteinuric kidney disease

Kidney podocytes and their foot processes maintain the ultrafiltration barrier and prevent urinary protein loss (proteinuria). Here we show that the GTPase dynamin is essential for podocyte function. During proteinuric kidney disease, induction of cytoplasmic cathepsin L leads to cleavage of dynamin at an evolutionary conserved site, resulting in reorganization of the podocyte actin cytoskeleton and proteinuria. Dynamin mutants that lack the cathepsin L site, or render the cathepsin L site inaccessible through dynamin self-assembly, are resistant to cathepsin L cleavage. When delivered into mice, these mutants restored podocyte function and resolve proteinuria. Our study identifies dynamin as a critical regulator of renal permselectivity that is specifically targeted by proteolysis under pathological conditions.

Image-guided tumor ablation: standardization of terminology and reporting criteria--a 10-year update.

Image-guided tumor ablation has become a well-established hallmark of local cancer therapy. The breadth of options available in this growing field increases the need for standardization of terminology and reporting criteria to facilitate effective communication of ideas and appropriate comparison among treatments that use different technologies, such as chemical (eg, ethanol or acetic acid) ablation, thermal therapies (eg, radiofrequency, laser, microwave, focused ultrasound, and cryoablation) and newer ablative modalities such as irreversible electroporation. This updated consensus document provides a framework that will facilitate the clearest communication among investigators regarding ablative technologies. An appropriate vehicle is proposed for reporting the various aspects of image-guided ablation therapy including classification of therapies, procedure terms, descriptors of imaging guidance, and terminology for imaging and pathologic findings. Methods are addressed for standardizing reporting of technique, follow-up, complications, and clinical results. As noted in the original document from 2003, adherence to the recommendations will improve the precision of communications in this field, leading to more accurate comparison of technologies and results, and ultimately to improved patient outcomes.

Quality Improvement Guidelines for the Performance of Inferior Vena Cava Filter Placement for the Prevention of Pulmonary Embolism

i PREAMBLE The membership of the Society of Interventional Radiology (SIR) Standards of Practice Committee represents experts in a broad spectrum of interventional procedures from both the private and academic sectors of medicine. Generally Standards of Practice Committee members dedicate the vast majority of their professional time to performing interventional procedures; as such they represent a valid broad expert constituency of the subject matter under consideration for standards production. Technical documents specifying the exact consensus and literature review methodologies as well as the institutional affiliations and professional credentials of the authors of this document are available upon request from SIR, 3975 Fair Ridge Dr., Suite 400 N., Fairfax, VA 22033.

Quality improvement guidelines for the treatment of lower-extremity deep vein thrombosis with use of endovascular thrombus removal.

Suresh Vedantham, MD, Patricia E. Thorpe, MD, John F. Cardella, MD, Chair, Clement J. Grassi, MD, Nilesh H. Patel, MD, Hector Ferral, MD, Lawrence V. Hofmann, MD, Bertrand M. Janne d’Othée, MD, Vittorio P. Antonaci, MD, Elias N. Brountzos, MD, Daniel B. Brown, MD, Louis G. Martin, MD, Alan H. Matsumoto, MD, Steven G. Meranze, MD, Donald L. Miller, MD, Steven F. Millward, MD, Robert J. Min, MD, Calvin D. Neithamer Jr., MD, Dheeraj K. Rajan, MD, Kenneth S. Rholl, MD, Marc S. Schwartzberg, MD, Timothy L. Swan, MD, Richard B. Towbin, MD, Bret N. Wiechmann, MD, and David Sacks, MD, for the CIRSE and SIR Standards of Practice Committees