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Contrast Ultrasound and Targeted Microbubbles: Diagnostic and Therapeutic Applications in Progressive Diabetic Nephropathy

  • Howard Leong-Poi
    Correspondence
    Address reprint requests to Howard Leong-Poi, MD, 6-044 Queen Wing, St. Michael's Hospital, 30 Bond St, Toronto, Ontario, Canada M5B 1W8
    Affiliations
    Division of Cardiology, Keenan Research Centre in the Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada
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      Summary

      Diabetic nephropathy remains one of the most common causes for end-stage renal disease worldwide. Although therapies aimed at optimizing glycemic control and systemic blood pressure have benefit, the reduction in progressive nephropathy remains modest at best. Thus, research continues to focus on newer therapies to address the unmet needs for additional renal protective strategies. The ability to noninvasively image the molecular and cellular processes that underlie diabetic nephropathy would be useful in risk stratifying patients with diabetes, and more importantly would aid in the evaluation of novel therapies to prevent and treat nephropathy. In addition, the development of ultrasound technologies that allow targeted gene delivery using high-power ultrasound and DNA-bearing microbubbles may have applicability for gene therapy to prevent diabetic nephropathy. This review highlights contrast-enhanced ultrasound imaging techniques for the evaluation of renal pathologies, including perfusion and molecular imaging techniques, and ultrasound-mediated gene delivery for therapeutic applications in diabetic nephropathy, that have potential for translation to clinical practice.

      Keywords

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      References

        • Rosolowsky E.T.
        • Skupien J.
        • Smiles A.M.
        • Niewczas M.
        • Roshan B.
        • Stanton R.
        • et al.
        Risk for ESRD in type 1 diabetes remains high despite renoprotection.
        J Am Soc Nephrol. 2011; 22: 545-553
        • Honos G.
        • Amyot R.
        • Choy J.
        • Leong-Poi H.
        • Schnell G.
        • Yu E.
        Contrast echocardiography in Canada: Canadian Cardiovascular Society/Canadian Society of Echocardiography position paper.
        Can J Cardiol. 2007; 23: 351-356
        • Wilson S.R.
        • Burns P.N.
        Microbubble-enhanced US in body imaging: what role?.
        Radiology. 2010; 257: 24-39
        • Young L.S.
        • Regan M.C.
        • Barry M.K.
        • Geraghty J.G.
        • Fitzpatrick J.M.
        Methods of renal blood flow measurement.
        Urol Res. 1996; 24: 149-160
        • Christiansen J.S.
        • Gammelgaard J.
        • Frandsen M.
        • Parving H.H.
        Increased kidney size, glomerular filtration rate and renal plasma flow in short-term insulin-dependent diabetics.
        Diabetologia. 1981; 20: 451-456
        • Singh A.K.
        • Gudehithlu K.P.
        • Pegoraro A.A.
        • Singh G.K.
        • Basheerudin K.
        • Robey R.B.
        • et al.
        Vascular factors altered in glucose-treated mesangial cells and diabetic glomeruli.
        Lab Invest. 2004; 84: 597-606
        • Juillard L.
        • Janier M.F.
        • Fouque D.
        • Cinotti L.
        • Maakel N.
        • Le Bars D.
        • et al.
        Dynamic renal blood flow measurement by positron emission tomography in patients with CRF.
        Am J Kidney Dis. 2002; 40: 947-954
        • Grenier N.
        • Quaia E.
        • Prasad P.V.
        • Juillard L.
        Radiology imaging of renal structure and function by computed tomography, magnetic resonance imaging, and ultrasound.
        Semin Nucl Med. 2011; 41: 45-60
        • Herget-Rosenthal S.
        Imaging techniques in the management of chronic kidney disease: current developments and future perspectives.
        Semin Nephrol. 2011; 31: 283-290
        • Lindner J.R.
        • Song J.
        • Jayaweera A.R.
        • Sklenar J.
        • Kaul S.
        Microvascular rheology of Definity microbubbles after intra-arterial and intravenous administration.
        J Am Soc Echocardiogr. 2002; 15: 396-403
        • Main M.L.
        • Goldman J.H.
        • Grayburn P.A.
        Thinking outside the “box”-the ultrasound contrast controversy.
        J Am Coll Cardiol. 2007; 50: 2434-2437
        • Dolan M.S.
        • Gala S.S.
        • Dodla S.
        • Abdelmoneim S.S.
        • Xie F.
        • Cloutier D.
        • et al.
        Safety and efficacy of commercially available ultrasound contrast agents for rest and stress echocardiography a multicenter experience.
        J Am Coll Cardiol. 2009; 53: 32-38
        • Wei K.
        • Jayaweera A.R.
        • Firoozan S.
        • Linka A.
        • Skyba D.M.
        • Kaul S.
        Quantification of myocardial blood flow with ultrasound-induced destruction of microbubbles administered as a constant venous infusion.
        Circulation. 1998; 97: 473-483
        • Wei K.
        • Le E.
        • Bin J.P.
        • Coggins M.
        • Thorpe J.
        • Kaul S.
        Quantification of renal blood flow with contrast-enhanced ultrasound.
        J Am Coll Cardiol. 2001; 37: 1135-1140
        • Kalantarinia K.
        • Belcik J.T.
        • Patrie J.T.
        • Wei K.
        Real-time measurement of renal blood flow in healthy subjects using contrast-enhanced ultrasound.
        Am J Physiol Renal Physiol. 2009; 297: F1129-F1134
        • Kolar R.
        • Jirik R.
        • Harabis V.
        • Mezl M.
        • Bartos M.
        Advanced methods for perfusion analysis in echocardiography.
        Physiol Res. 2010; 59: S33-S41
        • Kishimoto N.
        • Mori Y.
        • Nishiue T.
        • Nose A.
        • Kijima Y.
        • Tokoro T.
        • et al.
        Ultrasound evaluation of valsartan therapy for renal cortical perfusion.
        Hypertens Res. 2004; 27: 345-349
        • Leong-Poi H.
        Molecular imaging using contrast-enhanced ultrasound: evaluation of angiogenesis and cell therapy.
        Cardiovasc Res. 2009; 84: 190-200
        • Lindner J.R.
        • Song J.
        • Christiansen J.
        • Klibanov A.L.
        • Xu F.
        • Ley K.
        Ultrasound assessment of inflammation and renal tissue injury with microbubbles targeted to P-selectin.
        Circulation. 2001; 104: 2107-2112
        • Alonso A.
        • Della Martina A.
        • Stroick M.
        • Fatar M.
        • Griebe M.
        • Pochon S.
        • et al.
        Molecular imaging of human thrombus with novel abciximab immunobubbles and ultrasound.
        Stroke. 2007; 38: 1508-1514
        • Leong-Poi H.
        • Christiansen J.
        • Heppner P.
        • Lewis C.W.
        • Klibanov A.L.
        • Kaul S.
        • et al.
        Assessment of endogenous and therapeutic arteriogenesis by contrast ultrasound molecular imaging of integrin expression.
        Circulation. 2005; 111: 3248-3254
        • Kaufmann B.A.
        • Lewis C.
        • Xie A.
        • Mirza-Mohd A.
        • Lindner J.R.
        Detection of recent myocardial ischaemia by molecular imaging of P-selectin with targeted contrast echocardiography.
        Eur Heart J. 2007; 28: 2011-2017
        • Lin J.
        • Glynn R.J.
        • Rifai N.
        • Manson J.E.
        • Ridker P.M.
        • Nathan D.M.
        • et al.
        Inflammation and progressive nephropathy in type 1 diabetes in the diabetes control and complications trial.
        Diabetes Care. 2008; 31: 2338-2343
        • Navarro-Gonzalez J.F.
        • Mora-Fernandez C.
        • Muros de Fuentes M.
        • Garcia-Perez J.
        Inflammatory molecules and pathways in the pathogenesis of diabetic nephropathy.
        Nat Rev Nephrol. 2011; 7: 327-340
        • Lindner J.R.
        • Song J.
        • Xu F.
        • Klibanov A.L.
        • Singbartl K.
        • Ley K.
        • et al.
        Noninvasive ultrasound imaging of inflammation using microbubbles targeted to activated leukocytes.
        Circulation. 2000; 102: 2745-2750
        • Jing X.X.
        • Wang Z.G.
        • Ran H.T.
        • Li L.
        • Wu X.
        • Li X.D.
        • et al.
        Evaluation of renal ischemia-reperfusion injury in rabbits using microbubbles targeted to activated neutrophils.
        Clin Imaging. 2008; 32: 178-182
        • Kaufmann B.A.
        • Sanders J.M.
        • Davis C.
        • Xie A.
        • Aldred P.
        • Sarembock I.J.
        • et al.
        Molecular imaging of inflammation in atherosclerosis with targeted ultrasound detection of vascular cell adhesion molecule-1.
        Circulation. 2007; 116: 276-284
        • Yan Y.
        • Liao Y.
        • Yang L.
        • Wu J.
        • Du J.
        • Xuan W.
        • et al.
        Late-phase detection of recent myocardial ischaemia using ultrasound molecular imaging targeted to intercellular adhesion molecule-1.
        Cardiovasc Res. 2011; 89: 175-183
        • Zent R.
        • Pozzi A.
        Angiogenesis in diabetic nephropathy.
        Semin Nephrol. 2007; 27: 161-171
        • Nakagawa T.
        • Kosugi T.
        • Haneda M.
        • Rivard C.J.
        • Long D.A.
        Abnormal angiogenesis in diabetic nephropathy.
        Diabetes. 2009; 58: 1471-1478
        • Nyengaard J.R.
        • Rasch R.
        The impact of experimental diabetes mellitus in rats on glomerular capillary number and sizes.
        Diabetologia. 1993; 36: 189-194
        • Ichinose K.
        • Maeshima Y.
        • Yamamoto Y.
        • Kitayama H.
        • Takazawa Y.
        • Hirokoshi K.
        • et al.
        Antiangiogenic endostatin peptide ameliorates renal alterations in the early stage of a type 1 diabetic nephropathy model.
        Diabetes. 2005; 54: 2891-2903
        • Yamamoto Y.
        • Maeshima Y.
        • Kitayama H.
        • Kitamura S.
        • Takazawa Y.
        • Sugiyama H.
        • et al.
        Tumstatin peptide, an inhibitor of angiogenesis, prevents glomerular hypertrophy in the early stage of diabetic nephropathy.
        Diabetes. 2004; 53: 1831-1840
        • Hohenstein B.
        • Hausknecht B.
        • Boehmer K.
        • Riess R.
        • Brekken R.A.
        • Hugo C.P.
        Local VEGF activity but not VEGF expression is tightly regulated during diabetic nephropathy in man.
        Kidney Int. 2006; 69: 1654-1661
        • Korpanty G.
        • Carbon J.G.
        • Grayburn P.A.
        • Fleming J.B.
        • Brekken R.A.
        Monitoring response to anticancer therapy by targeting microbubbles to tumor vasculature.
        Clin Cancer Res. 2007; 13: 323-330
        • Leong-Poi H.
        • Christiansen J.
        • Klibanov A.L.
        • Kaul S.
        • Lindner J.R.
        Noninvasive assessment of angiogenesis by ultrasound and microbubbles targeted to alpha(v)-integrins.
        Circulation. 2003; 107: 455-460
        • Eliceiri B.P.
        • Cheresh D.A.
        The role of alphav integrins during angiogenesis: insights into potential mechanisms of action and clinical development.
        J Clin Invest. 1999; 103: 1227-1230
        • Matsui T.
        • Nishino Y.
        • Maeda S.
        • Takeuchi M.
        • Yamagishi S.
        Irbesartan inhibits advanced glycation end product (AGE)-induced up-regulation of vascular cell adhesion molecule-1 (VCAM-1) mRNA levels in glomerular endothelial cells.
        Microvasc Res. 2011; 81: 269-273
        • Ina K.
        • Kitamura H.
        • Okeda T.
        • Nagai K.
        • Liu Z.Y.
        • Matsuda M.
        • et al.
        Vascular cell adhesion molecule-1 expression in the renal interstitium of diabetic KKAy mice.
        Diabetes Res Clin Pract. 1999; 44: 1-8
        • Jin D.K.
        • Fish A.J.
        • Wayner E.A.
        • Mauer M.
        • Setty S.
        • Tsilibary E.
        • et al.
        Distribution of integrin subunits in human diabetic kidneys.
        J Am Soc Nephrol. 1996; 7: 2636-2645
        • Stewart D.J.
        • Kutryk M.J.
        • Fitchett D.
        • Freeman M.
        • Camack N.
        • Su Y.
        • et al.
        VEGF gene therapy fails to improve perfusion of ischemic myocardium in patients with advanced coronary disease: results of the NORTHERN trial.
        Mol Ther. 2009; 17: 1109-1115
        • Simons M.
        • Bonow R.O.
        • Chronos N.A.
        • Cohen D.J.
        • Giordano F.J.
        • Hammond H.K.
        • et al.
        Clinical trials in coronary angiogenesis: issues, problems, consensus: an expert panel summary.
        Circulation. 2000; 102: E73-E86
        • Isaka Y.
        Gene therapy targeting kidney diseases: routes and vehicles.
        Clin Exp Nephrol. 2006; 10: 229-235
        • van der Wouden E.A.
        • Sandovici M.
        • Henning R.H.
        • de Zeeuw D.
        • Deelman L.E.
        Approaches and methods in gene therapy for kidney disease.
        J Pharmacol Toxicol Methods. 2004; 50: 13-24
        • Grines C.L.
        • Watkins M.W.
        • Mahmarian J.J.
        • Iskandrian A.E.
        • Rade J.J.
        • Marrott P.
        • et al.
        A randomized, double-blind, placebo-controlled trial of Ad5FGF-4 gene therapy and its effect on myocardial perfusion in patients with stable angina.
        J Am Coll Cardiol. 2003; 42: 1339-1347
        • Losordo D.W.
        • Vale P.R.
        • Symes J.F.
        • Dunnington C.H.
        • Esakof D.D.
        • Maysky M.
        • et al.
        Gene therapy for myocardial angiogenesis: initial clinical results with direct myocardial injection of phVEGF165 as sole therapy for myocardial ischemia.
        Circulation. 1998; 98: 2800-2804
        • Smith A.H.
        • Fujii H.
        • Kuliszewski M.A.
        • Leong-Poi H.
        Contrast ultrasound and targeted microbubbles: diagnostic and therapeutic applications for angiogenesis.
        J Cardiovasc Transl Res. 2011; 4: 404-415
        • Bekeredjian R.
        • Chen S.
        • Frenkel P.A.
        • Grayburn P.A.
        • Shohet R.V.
        Ultrasound-targeted microbubble destruction can repeatedly direct highly specific plasmid expression to the heart.
        Circulation. 2003; 108: 1022-1026
        • Christiansen J.P.
        • French B.A.
        • Klibanov A.L.
        • Kaul S.
        • Lindner J.R.
        Targeted tissue transfection with ultrasound destruction of plasmid-bearing cationic microbubbles.
        Ultrasound Med Biol. 2003; 29: 1759-1767
        • Kodama T.
        • Tomita Y.
        • Koshiyama K.
        • Blomley M.J.
        Transfection effect of microbubbles on cells in superposed ultrasound waves and behavior of cavitation bubble.
        Ultrasound Med Biol. 2006; 32: 905-914
        • Chen S.
        • Shohet R.V.
        • Bekeredjian R.
        • Frenkel P.
        • Grayburn P.A.
        Optimization of ultrasound parameters for cardiac gene delivery of adenoviral or plasmid deoxyribonucleic acid by ultrasound-targeted microbubble destruction.
        J Am Coll Cardiol. 2003; 42: 301-308
        • Leong-Poi H.
        • Kuliszewski M.A.
        • Lekas M.
        • Sibbald M.
        • Teichert-Kuliszewska K.
        • Klibanov A.L.
        • et al.
        Therapeutic arteriogenesis by ultrasound-mediated VEGF165 plasmid gene delivery to chronically ischemic skeletal muscle.
        Circ Res. 2007; 101: 295-303
        • Korpanty G.
        • Chen S.
        • Shohet R.V.
        • Ding J.
        • Yang B.
        • Frenkel P.A.
        • et al.
        Targeting of VEGF-mediated angiogenesis to rat myocardium using ultrasonic destruction of microbubbles.
        Gene Ther. 2005; 12: 1305-1312
        • Suzuki J.
        • Ogawa M.
        • Takayama K.
        • Taniyama Y.
        • Morishita R.
        • Hirata Y.
        • et al.
        Ultrasound-microbubble-mediated intercellular adhesion molecule-1 small interfering ribonucleic acid transfection attenuates neointimal formation after arterial injury in mice.
        J Am Coll Cardiol. 2010; 55: 904-913
        • Song J.
        • Chappell J.C.
        • Qi M.
        • VanGieson E.J.
        • Kaul S.
        • Price R.J.
        Influence of injection site, microvascular pressure and ultrasound variables on microbubble-mediated delivery of microspheres to muscle.
        J Am Coll Cardiol. 2002; 39: 726-731
        • Williams A.R.
        • Wiggins R.C.
        • Wharram B.L.
        • Goyal M.
        • Dou C.
        • Johnson K.J.
        • et al.
        Nephron injury induced by diagnostic ultrasound imaging at high mechanical index with gas body contrast agent.
        Ultrasound Med Biol. 2007; 33: 1336-1344
        • Kobulnik J.
        • Kuliszewski M.A.
        • Stewart D.J.
        • Lindner J.R.
        • Leong-Poi H.
        Comparison of gene delivery techniques for therapeutic angiogenesis ultrasound-mediated destruction of carrier microbubbles versus direct intramuscular injection.
        J Am Coll Cardiol. 2009; 54: 1735-1742
        • Fujii H.
        • Li S.H.
        • Wu J.
        • Miyagi Y.
        • Yau T.M.
        • Rakowski H.
        • et al.
        Repeated and targeted transfer of angiogenic plasmids into the infarcted rat heart via ultrasound targeted microbubble destruction enhances cardiac repair.
        Eur Heart J. 2011; 32: 2075-2084
        • Kuliszewski M.A.
        • Kobulnik J.
        • Lindner J.R.
        • Stewart D.J.
        • Leong-Poi H.
        Vascular gene transfer of SDF-1 promotes endothelial progenitor cell engraftment and enhances angiogenesis in ischemic muscle.
        Mol Ther. 2011; 19: 895-902
        • Cruzado J.M.
        • Lloberas N.
        • Torras J.
        • Riera M.
        • Fillat C.
        • Herrero-Fresneda I.
        • et al.
        Regression of advanced diabetic nephropathy by hepatocyte growth factor gene therapy in rats.
        Diabetes. 2004; 53: 1119-1127
        • Chen H.Y.
        • Huang X.R.
        • Wang W.
        • Li J.H.
        • Heuchel R.L.
        • Chung A.C.
        • et al.
        The protective role of Smad7 in diabetic kidney disease: mechanism and therapeutic potential.
        Diabetes. 2011; 60: 590-601
        • Zhang Z.
        • Wu F.
        • Zheng F.
        • Li H.
        Adenovirus-mediated decorin gene transfection has therapeutic effects in a streptozocin-induced diabetic rat model.
        Nephron Exp Nephrol. 2010; 116: e11-e21
        • Lan H.Y.
        • Mu W.
        • Tomita N.
        • Huang X.R.
        • Li J.H.
        • Zhu H.J.
        • et al.
        Inhibition of renal fibrosis by gene transfer of inducible Smad7 using ultrasound-microbubble system in rat UUO model.
        J Am Soc Nephrol. 2003; 14: 1535-1548
        • Hou C.C.
        • Wang W.
        • Huang X.R.
        • Fu P.
        • Chen T.H.
        • Sheikh-Hamad D.
        • et al.
        Ultrasound-microbubble-mediated gene transfer of inducible Smad7 blocks transforming growth factor-beta signaling and fibrosis in rat remnant kidney.
        Am J Pathol. 2005; 166: 761-771
        • Azuma H.
        • Tomita N.
        • Kaneda Y.
        • Koike H.
        • Ogihara T.
        • Katsuoka Y.
        • et al.
        Transfection of NFkappaB-decoy oligodeoxynucleotides using efficient ultrasound-mediated gene transfer into donor kidneys prolonged survival of rat renal allografts.
        Gene Ther. 2003; 10: 415-425
        • Chen S.
        • Ding J.
        • Yu C.
        • Yang B.
        • Wood D.R.
        • Grayburn P.A.
        Reversal of streptozotocin-induced diabetes in rats by gene therapy with betacellulin and pancreatic duodenal homeobox-1.
        Gene Ther. 2007; 14: 1102-1110
        • Chen S.
        • Ding J.H.
        • Bekeredjian R.
        • Yang B.Z.
        • Shohet R.V.
        • Johnston S.A.
        • et al.
        Efficient gene delivery to pancreatic islets with ultrasonic microbubble destruction technology.
        Proc Natl Acad Sci U S A. 2006; 103: 8469-8474
        • Ahn J.D.
        • Morishita R.
        • Kaneda Y.
        • Kim H.J.
        • Kim Y.D.
        • Lee H.J.
        • et al.
        Transcription factor decoy for AP-1 reduces mesangial cell proliferation and extracellular matrix production in vitro and in vivo.
        Gene Ther. 2004; 11: 916-923
        • Kagawa T.
        • Takemura G.
        • Kosai K.
        • Murata I.
        • Ohno T.
        • Takahashi T.
        • et al.
        Hepatocyte growth factor gene therapy slows down the progression of diabetic nephropathy in db/db mice.
        Nephron Physiol. 2006; 102: 92-102
        • Zhang Y.
        • Wada J.
        • Hashimoto I.
        • Eguchi J.
        • Yasuhara A.
        • Kanwar Y.S.
        • et al.
        Therapeutic approach for diabetic nephropathy using gene delivery of translocase of inner mitochondrial membrane 44 by reducing mitochondrial superoxide production.
        J Am Soc Nephrol. 2006; 17: 1090-1101
        • Kondo T.
        • Takemura G.
        • Kosai K.
        • Ohno T.
        • Takahashi T.
        • Esaki M.
        • et al.
        Application of an adenoviral vector encoding soluble transforming growth factor-beta type II receptor to the treatment of diabetic nephropathy in mice.
        Clin Exp Pharmacol Physiol. 2008; 35: 1288-1293
        • Kosugi T.
        • Nakayama T.
        • Li Q.
        • Chiodo V.A.
        • Zhang L.
        • Campbell-Thompson M.
        • et al.
        Soluble Flt-1 gene therapy ameliorates albuminuria but accelerates tubulointerstitial injury in diabetic mice.
        Am J Physiol Renal Physiol. 2010; 298: F609-F616
        • Long J.
        • Wang Y.
        • Wang W.
        • Chang B.H.
        • Danesh F.R.
        MicroRNA-29c is a signature microRNA under high glucose conditions that targets Sprouty homolog 1, and its in vivo knockdown prevents progression of diabetic nephropathy.
        J Biol Chem. 2011; 286: 11837-11848
        • Saito D.
        • Maeshima Y.
        • Nasu T.
        • Yamasaki H.
        • Tanabe K.
        • Sugiyama H.
        • et al.
        Amelioration of renal alterations in obese type 2 diabetic mice by vasohibin-1, a negative feedback regulator of angiogenesis.
        Am J Physiol Renal Physiol. 2011; 300: F873-F886