Horizon 2020 in Diabetic Kidney Disease: The Clinical Trial Pipeline for Add-On Therapies on Top of Renin Angiotensin System Blockade

Maria Vanessa Perez-Gomez, Maria Dolores Sanchez-Niño, Ana Belen Sanz, Catalina Martín-Cleary, Marta Ruiz-Ortega, Jesus Egido, Juan F Navarro-González, Alberto Ortiz, Beatriz Fernandez-Fernandez, Maria Vanessa Perez-Gomez, Maria Dolores Sanchez-Niño, Ana Belen Sanz, Catalina Martín-Cleary, Marta Ruiz-Ortega, Jesus Egido, Juan F Navarro-González, Alberto Ortiz, Beatriz Fernandez-Fernandez

Abstract

Diabetic kidney disease is the most frequent cause of end-stage renal disease. This implies failure of current therapeutic approaches based on renin-angiotensin system (RAS) blockade. Recent phase 3 clinical trials of paricalcitol in early diabetic kidney disease and bardoxolone methyl in advanced diabetic kidney disease failed to meet the primary endpoint or terminated on safety concerns, respectively. However, various novel strategies are undergoing phase 2 and 3 randomized controlled trials targeting inflammation, fibrosis and signaling pathways. Among agents currently undergoing trials that may modify the clinical practice on top of RAS blockade in a 5-year horizon, anti-inflammatory agents currently hold the most promise while anti-fibrotic agents have so far disappointed. Pentoxifylline, an anti-inflammatory agent already in clinical use, was recently reported to delay estimated glomerular filtration rate (eGFR) loss in chronic kidney disease (CKD) stage 3-4 diabetic kidney disease when associated with RAS blockade and promising phase 2 data are available for the pentoxifylline derivative CTP-499. Among agents targeting chemokines or chemokine receptors, the oral small molecule C-C chemokine receptor type 2 (CCR2) inhibitor CCX140 decreased albuminuria and eGFR loss in phase 2 trials. A dose-finding trial of the anti-IL-1β antibody gevokizumab in diabetic kidney disease will start in 2015. However, clinical development is most advanced for the endothelin receptor A blocker atrasentan, which is undergoing a phase 3 trial with a primary outcome of preserving eGFR. The potential for success of these approaches and other pipeline agents is discussed in detail.

Keywords: chronic kidney disease; diabetes; diabetic kidney disease; inflammation; interleukin-1-beta; treatment.

Figures

Figure 1
Figure 1
Promising therapeutic approaches to diabetic kidney disease (DKD) undergoing clinical trials. Only drugs and targets under active clinical investigation are shown. Renin angiotensin system (RAS) targeting drugs not shown as they are already in clinical use. MR: mineralocorticoid receptor. ETA: Endothelin receptor A.

References

    1. GBD 2013 Mortality and Causes of Death Collaborators Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990–2013: A systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2015;385:117–171.
    1. Wild S., Roglic G., Green A., Sicree R., King H. Global prevalence of diabetes: Estimates for the year 2000 and projections for 2030. Diabetes Care. 2004;27:1047–1053.
    1. Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney Int. Suppl. 2013;3:1–150.
    1. United States Renal Data System (USRDS) 2014 Annual Data Report. [(accessed on 29 March 2015)]. Available online: .
    1. de Boer I.H., Rue T.C., Hall Y.N., Heagerty P.J., Weiss N.S., Himmelfarb J. Temporal trends in the prevalence of diabetic kidney disease in the United States. JAMA. 2011;305:2532–2539. doi: 10.1001/jama.2011.861.
    1. Ortiz A. Translational nephrology: What translational research is and a bird’s-eye view on translational research in nephrology. Clin. Kidney J. 2015;8:14–22. doi: 10.1093/ckj/sfu142.
    1. Fernandez-Fernandez B., Ortiz A., Gomez-Guerrero C., Egido J. Therapeutic approaches to diabetic nephropathy—Beyond the RAS. Nat. Rev. Nephrol. 2014;10:325–346. doi: 10.1038/nrneph.2014.74.
    1. . [(accessed on 2 April 2015)]; Available online: .
    1. de Boer I.H., Rue T.C., Cleary P.A., Lachin J.M., Molitch M.E., Steffes M.W., Sun W., Zinman B., Brunzell J.D., White N.H., et al. Long-term renal outcomes of patients with type 1 diabetes mellitus and microalbuminuria: An analysis of the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications cohort. Arch. Intern. Med. 2011;171:412–420. doi: 10.1001/archinternmed.2011.16.
    1. Molitch M.E., Steffes M., Sun W., Rutledge B., Cleary P., de Boer I.H., Zinman B., Lachin J. Development and progression of renal insufficiency with and without albuminuria in adults with type 1 diabetes in the diabetes control and complications trial and the epidemiology of diabetes interventions and complications study. Diabetes Care. 2010;33:1536–1543. doi: 10.2337/dc09-1098.
    1. Retnakaran R., Cull C.A., Thorne K.I., Adler A.I., Holman R.R. Risk factors for renal dysfunction in type 2 diabetes: U.K. Prospective Diabetes Study 74. Diabetes. 2006;55:1832–1839. doi: 10.2337/db05-1620.
    1. Kramer H.J., Nguyen Q.D., Curhan G., Hsu C.Y. Renal insufficiency in the absence of albuminuria and retinopathy among adults with type 2 diabetes mellitus. JAMA. 2003;289:3273–3277. doi: 10.1001/jama.289.24.3273.
    1. Ekinci E.I., Jerums G., Skene A., Crammer P., Power D., Cheong K.Y., Panagiotopoulos S., McNeil K., Baker S.T., Fioretto P., et al. Renal structure in normoalbuminuric and albuminuric patients with type 2 diabetes and impaired renal function. Diabetes Care. 2013;36:3620–3626. doi: 10.2337/dc12-2572.
    1. Justo P., Sanz A.B., Egido J., Ortiz A. 3,4-Dideoxyglucosone-3-ene induces apoptosis in renal tubular epithelial cells. Diabetes. 2005;54:2424–2429. doi: 10.2337/diabetes.54.8.2424.
    1. Sanchez-Nino M.D., Sanz A.B., Lorz C., Gnirke A., Rastaldi M.P., Nair V., Egido J., Ruiz-Ortega M., Kretzler M., Ortiz A. BASP1 promotes apoptosis in diabetic nephropathy. J. Am. Soc. Nephrol. 2010;21:610–621. doi: 10.1681/ASN.2009020227.
    1. Haller H., Ito S., Izzo J.L., Jr., Januszewicz A., Katayama S., Menne J., Mimran A., Rabelink T.J., Ritz E., Ruilope L.M., et al. Olmesartan for the delay or prevention of microalbuminuria in type 2 diabetes. N. Engl. J. Med. 2011;364:907–917. doi: 10.1056/NEJMoa1007994.
    1. American Diabetes Association Standards of medical care in diabetes—2014. Diabetes Care. 2014;37:S14–S80.
    1. Fried L.F., Emanuele N., Zhang J.H., Brophy M., Conner T.A., Duckworth W., Leehey D.J., McCullough P.A., O’Connor T., Palevsky P.M., et al. Combined angiotensin inhibition for the treatment of diabetic nephropathy. N. Engl. J. Med. 2013;369:1892–1903. doi: 10.1056/NEJMoa1303154.
    1. Mann J.F., Schmieder R.E., McQueen M., Dyal L., Schumacher H., Pogue J., Wang X., Maggioni A., Budaj A., Chaithiraphan S., et al. Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): A multicentre, randomised, double-blind, controlled trial. Lancet. 2008;372:547–553. doi: 10.1016/S0140-6736(08)61236-2.
    1. Gentile G., Remuzzi G., Ruggenenti P. Dual renin-angiotensin system blockade for nephroprotection: Still under scrutiny. Nephron. 2015;129:39–41. doi: 10.1159/000368331.
    1. Esteras R., Perez-Gomez M.V., Rodriguez-Osorio L., Ortiz A., Fernandez-Fernandez B. Combination use of medicines from two classes of RAS blocking agents: Risk of hyperkalaemia, hypotension, and impaired renal function. Ther. Adva. Drug Saf. (accepted)
    1. Raval A.D., Thakker D., Rangoonwala A.N., Gor D., Walia R. Vitamin B and its derivatives for diabetic kidney disease. Cochrane Database Syst. Rev. 2015;1 doi: 10.1002/14651858.CD009403.pub2.
    1. . [(accessed on 29 March 2015)]; Available online: .
    1. Lewis E.J., Greene T., Spitalewiz S., Blumenthal S., Berl T., Hunsicker L.G., Pohl M.A., Rohde R.D., Raz I., Yerushalmy Y., et al. Pyridorin in type 2 diabetic nephropathy. J. Am. Soc. Nephrol. 2012;23:131–136. doi: 10.1681/ASN.2011030272.
    1. Navarro-Gonzalez J.F., Muros M., Mora-Fernandez C., Herrera H., Meneses B., Garcia J. Pentoxifylline for renoprotection in diabetic nephropathy: The PREDIAN study. Rationale and basal results. J. Diabetes Complicat. 2011;25:314–319. doi: 10.1016/j.jdiacomp.2010.09.003.
    1. de Zeeuw D., Agarwal R., Amdahl M., Audhya P., Coyne D., Garimella T., Parving H.H., Pritchett Y., Remuzzi G., Ritz E., et al. Selective vitamin D receptor activation with paricalcitol for reduction of albuminuria in patients with type 2 diabetes (VITAL study): A randomised controlled trial. Lancet. 2010;376:1543–1551. doi: 10.1016/S0140-6736(10)61032-X.
    1. Kohan D.E., Pritchett Y., Molitch M., Wen S., Garimella T., Audhya P., Andress D.L. Addition of atrasentan to renin-angiotensin system blockade reduces albuminuria in diabetic nephropathy. J Am. Soc. Nephrol. 2011;22:763–772. doi: 10.1681/ASN.2010080869.
    1. Lewis E.J., Lewis J.B., Greene T., Hunsicker L.G., Berl T., Pohl M.A., de Zeeuw D., Heerspink H.L., Rohde R.D., Atkins R.C., et al. Sulodexide for kidney protection in type 2 diabetes patients with microalbuminuria: A randomized controlled trial. Am. J. Kidney Dis. 2011;58:729–736. doi: 10.1053/j.ajkd.2011.06.020.
    1. Pergola P.E., Raskin P., Toto R.D., Meyer C.J., Huff J.W., Grossman E.B., Krauth M., Ruiz S., Audhya P., Christ-Schmidt H., et al. Bardoxolone methyl and kidney function in CKD with type 2 diabetes. N. Engl. J. Med. 2011;365:327–336. doi: 10.1056/NEJMoa1105351.
    1. Tumlin J.A., Galphin C.M., Rovin B.H. Advanced diabetic nephropathy with nephrotic range proteinuria: A pilot study of the long-term efficacy of subcutaneous ACTH gel on proteinuria, progression of CKD, and urinary levels of VEGF and MCP-1. J. Diabetes Res. 2013;2013 doi: 10.1155/2013/489869.
    1. Tuttle K.R., Bakris G.L., Toto R.D., McGill J.B., Hu K., Anderson P.W. The effect of ruboxistaurin on nephropathy in type 2 diabetes. Diabetes Care. 2005;28:2686–2690. doi: 10.2337/diacare.28.11.2686.
    1. Coresh J., Turin T.C., Matsushita K., Sang Y., Ballew S.H., Appel L.J., Arima H., Chadban S.J., Cirillo M., Djurdjev O., et al. Decline in estimated glomerular filtration rate and subsequent risk of end-stage renal disease and mortality. JAMA. 2014;311:2518–2531. doi: 10.1001/jama.2014.6634.
    1. Perez-Gomez M.V., Ortiz-Arduan A., Lorenzo-Sellares V. Vitamin D and proteinuria: A critical review of molecular bases and clinical experience. Nefrologia. 2013;33:716–726.
    1. Sanchez-Nino M.D., Bozic M., Cordoba-Lanus E., Valcheva P., Gracia O., Ibarz M., Fernandez E., Navarro-Gonzalez J.F., Ortiz A., Valdivielso J.M. Beyond proteinuria: VDR activation reduces renal inflammation in experimental diabetic nephropathy. Am. J. Physiol. Renal. Physiol. 2012;302:F647–F657. doi: 10.1152/ajprenal.00090.2011.
    1. Sanchez-Nino M.D., Sanz A.B., Carrasco S., Saleem M.A., Mathieson P.W., Valdivielso J.M., Ruiz-Ortega M., Egido J., Ortiz A. Globotriaosylsphingosine actions on human glomerular podocytes: Implications for Fabry nephropathy. Nephrol. Dial. Transplant. 2011;26:1797–1802. doi: 10.1093/ndt/gfq306.
    1. Alborzi P., Patel N.A., Peterson C., Bills J.E., Bekele D.M., Bunaye Z., Light R.P., Agarwal R. Paricalcitol reduces albuminuria and inflammation in chronic kidney disease: A randomized double-blind pilot trial. Hypertension. 2008;52:249–255. doi: 10.1161/HYPERTENSIONAHA.108.113159.
    1. Fishbane S., Chittineni H., Packman M., Dutka P., Ali N., Durie N. Oral paricalcitol in the treatment of patients with CKD and proteinuria: A randomized trial. Am. J. Kidney Dis. 2009;54:647–652. doi: 10.1053/j.ajkd.2009.04.036.
    1. Gonzalez E., Rojas-Rivera J., Polanco N., Morales E., Morales J.M., Egido J., Amado A., Praga M. Effects of oral paricalcitol on secondary hyperparathyroidism and proteinuria of kidney transplant patients. Transplantation. 2013;95:e49–e52. doi: 10.1097/TP.0b013e3182855565.
    1. Ortiz A., Sanchez-Nino M.D., Rojas J., Egido J. Paricalcitol for reduction of albuminuria in diabetes. Lancet. 2011;377:635–636. doi: 10.1016/S0140-6736(11)60224-9.
    1. Gomez-Garre D., Largo R., Liu X.H., Gutierrez S., Lopez-Armada M.J., Palacios I., Egido J. An orally active ETA/ETB receptor antagonist ameliorates proteinuria and glomerular lesions in rats with proliferative nephritis. Kidney Int. 1996;50:962–972. doi: 10.1038/ki.1996.397.
    1. Gomez-Garre D., Largo R., Tejera N., Fortes J., Manzarbeitia F., Egido J. Activation of NF-kappaB in tubular epithelial cells of rats with intense proteinuria: Role of angiotensin II and endothelin-1. Hypertension. 2001;37:1171–1178. doi: 10.1161/01.HYP.37.4.1171.
    1. Rodriguez-Vita J., Ruiz-Ortega M., Ruperez M., Esteban V., Sanchez-Lopez E., Plaza J.J., Egido J. Endothelin-1, via ETA receptor and independently of transforming growth factor-beta, increases the connective tissue growth factor in vascular smooth muscle cells. Circ. Res. 2005;97:125–134. doi: 10.1161/01.RES.0000174614.74469.83.
    1. Mann J.F., Green D., Jamerson K., Ruilope L.M., Kuranoff S.J., Littke T., Viberti G., ASCEND Study Group Avosentan for overt diabetic nephropathy. J. Am. Soc. Nephrol. 2010;21:527–535. doi: 10.1681/ASN.2009060593.
    1. de Zeeuw D., Coll B., Andress D., Brennan J.J., Tang H., Houser M., Correa-Rotter R., Kohan D., Lambers Heerspink H.J., Makino H., et al. The endothelin antagonist atrasentan lowers residual albuminuria in patients with type 2 diabetic nephropathy. J. Am. Soc. Nephrol. 2014;25:1083–1093. doi: 10.1681/ASN.2013080830.
    1. Brem A.S., Morris D.J., Gong R. Aldosterone-induced fibrosis in the kidney: Questions and controversies. Am. J. Kidney Dis. 2011;58:471–479. doi: 10.1053/j.ajkd.2011.03.029.
    1. Ruilope L.M., Agarwal R., Chan J.C., Cooper M.E., Gansevoort R.T., Haller H., Remuzzi G., Rossing P., Schmieder R.E., Nowack C., et al. Rationale, design, and baseline characteristics of ARTS-DN: A randomized study to assess the safety and efficacy of finerenone in patients with type 2 diabetes mellitus and a clinical diagnosis of diabetic nephropathy. Am. J. Nephrol. 2014;40:572–581. doi: 10.1159/000371497.
    1. Rossing K., Schjoedt K.J., Smidt U.M., Boomsma F., Parving H.H. Beneficial effects of adding spironolactone to recommended antihypertensive treatment in diabetic nephropathy: A randomized, double-masked, cross-over study. Diabetes Care. 2005;28:2106–2112. doi: 10.2337/diacare.28.9.2106.
    1. Siwy J., Schanstra J.P., Argiles A., Bakker S.J., Beige J., Boucek P., Brand K., Delles C., Duranton F., Fernandez-Fernandez B., et al. Multicentre pective validation of a urinary peptidome-based classifier for the diagnosis of type 2 diaprosbetic nephropathy. Nephrol. Dial. Transplant. 2014;29:1563–1570. doi: 10.1093/ndt/gfu039.
    1. European Union Proteomic prediction and Renin angiotensin aldosterone system Inhibition prevention Of early diabetic nephRopathy In TYpe 2 diabetic patients with normoalbuminuria (PRIORITY) [(accessed on 29 March 2015)]. Available online:
    1. Epstein M. Mineralocorticoid receptor antagonists: Part of an emerging treatment paradigm for chronic kidney disease. Lancet Diabetes Endocrinol. 2014;2:925–927. doi: 10.1016/S2213-8587(14)70216-5.
    1. Bakris G., Nowack C., Ruilope L.M. Results of ARTS-DN: A Randomized Study to Assess the Safety and Efficacy of Finerenone in Patients with Type 2 Diabetes and Diabetic Nephropahty. World Congress of Nephrology; Cape Town, South Africa: 2015.
    1. Ficociello L.H., Rosolowsky E.T., Niewczas M.A., Maselli N.J., Weinberg J.M., Aschengrau A., Eckfeldt J.H., Stanton R.C., Galecki A.T., Doria A., et al. High-normal serum uric acid increases risk of early progressive renal function loss in type 1 diabetes: Results of a 6-year follow-up. Diabetes Care. 2010;33:1337–1343. doi: 10.2337/dc10-0227.
    1. Goicoechea M., de Vinuesa S.G., Verdalles U., Ruiz-Caro C., Ampuero J., Rincon A., Arroyo D., Luno J. Effect of allopurinol in chronic kidney disease progression and cardiovascular risk. Clin. J. Am. Soc. Nephrol. 2010;5:1388–1393. doi: 10.2215/CJN.01580210.
    1. Maahs D.M., Caramori L., Cherney D.Z., Galecki A.T., Gao C., Jalal D., Perkins B.A., Pop-Busui R., Rossing P., Mauer M., et al. Uric acid lowering to prevent kidney function loss in diabetes: The preventing early renal function loss (PERL) allopurinol study. Curr. Diab. Rep. 2013;13:550–559. doi: 10.1007/s11892-013-0381-0.
    1. Hosoya T., Kimura K., Itoh S., Inaba M., Uchida S., Tomino Y., Makino H., Matsuo S., Yamamoto T., Ohno I., et al. The effect of febuxostat to prevent a further reduction in renal function of patients with hyperuricemia who have never had gout and are complicated by chronic kidney disease stage 3: Study protocol for a multicenter randomized controlled study. Trials. 2014;15 doi: 10.1186/1745-6215-15-26.
    1. Ghorbani A., Omidvar B., Beladi-Mousavi S.S., Lak E., Vaziri S. The effect of pentoxifylline on reduction of proteinuria among patients with type 2 diabetes under blockade of angiotensin system: A double blind and randomized clinical trial. Nefrologia. 2012;32:790–796.
    1. Navarro-Gonzalez J.F., Mora-Fernandez C., Muros de Fuentes F.M., Chahin J., Mendez M.L., Gallego E., Macia M., del Castillo C.N., Rivero A., Getino M.A., et al. Effect of pentoxifylline on renal function and urinary albumin excretion in patients with diabetic kidney disease: The PREDIAN trial. J. Am. Soc. Nephrol. 2015;26:220–229. doi: 10.1681/ASN.2014010012.
    1. Tang X., Bridson G., Ke J., Wu L., Erol H., Graham P., Lin C.H., Braman V., Zhao H., Liu J.F., et al. Quantitative analyses of CTP-499 and five major metabolites by core-structure analysis. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 2014;963:1–9. doi: 10.1016/j.jchromb.2014.05.043.
    1. Singh B., Diamond S.A., Pergola S.E., Shipley J.E., Wu L., Sabounjian L.A., Graham P.B. Effect of CTP-499 on renal function in patients with type 2 diabetes and kidney disease. Am. J. Kidney Dis. 2014;63:A1–A120.
    1. Kidney Week Selective inhibition of phosphodiesterase type 5 reduces macroalbuminuira in subjects with type 2 diabetes, and overt nephropathy; Proceedings of the Kidney Week 2014: American Society of Nephrology Annual Meeting; Philadelphia, PA, USA. 11–16 November 2014.
    1. Park S.Y., Rhee S.Y., Oh S., Kwon H.S., Cha B.Y., Lee H.J., Lee H.C., Kim Y.S. Evaluation of the effectiveness of sarpogrelate on the surrogate markers for macrovascular complications in patients with type 2 diabetes. Endocr. J. 2012;59:709–716. doi: 10.1507/endocrj.EJ12-0047.
    1. Kasho M., Sakai M., Sasahara T., Anami Y., Matsumura T., Takemura T., Matsuda H., Kobori S., Shichiri M. Serotonin enhances the production of type IV collagen by human mesangial cells. Kidney Int. 1998;54:1083–1092. doi: 10.1046/j.1523-1755.1998.00114.x.
    1. Kobayashi S., Satoh M., Namikoshi T., Haruna Y., Fujimoto S., Arakawa S., Komai N., Tomita N., Sasaki T., Kashihara N. Blockade of serotonin 2A receptor improves glomerular endothelial function in rats with streptozotocin-induced diabetic nephropathy. Clin. Exp. Nephrol. 2008;12:119–125. doi: 10.1007/s10157-007-0011-8.
    1. Kanai H., Hiromura K., Kuroiwa T., Maezawa A., Yano S., Naruse T. Role of serotonin in nephrotoxic serum nephritis in WKY rats. J. Lab. Clin. Med. 1997;129:557–566. doi: 10.1016/S0022-2143(97)90010-X.
    1. Hamasaki Y., Doi K., Maeda-Mamiya R., Ogasawara E., Katagiri D., Tanaka T., Yamamoto T., Sugaya T., Nangaku M., Noiri E. A 5-hydroxytryptamine receptor antagonist, sarpogrelate, reduces renal tubulointerstitial fibrosis by suppressing PAI-1. Am. J. Physiol. Renal. Physiol. 2013;305:F1796–F1803. doi: 10.1152/ajprenal.00151.2013.
    1. Ruiz S., Pergola P.E., Zager R.A., Vaziri N.D. Targeting the transcription factor Nrf2 to ameliorate oxidative stress and inflammation in chronic kidney disease. Kidney Int. 2013;83:1029–1041. doi: 10.1038/ki.2012.439.
    1. de Zeeuw D., Akizawa T., Audhya P., Bakris G.L., Chin M., Christ-Schmidt H., Goldsberry A., Houser M., Krauth M., Lambers Heerspink H.J., et al. Bardoxolone methyl in type 2 diabetes and stage 4 chronic kidney disease. N. Engl. J. Med. 2013;369:2492–2503. doi: 10.1056/NEJMoa1306033.
    1. Zoja C., Corna D., Nava V., Locatelli M., Abbate M., Gaspari F., Carrara F., Sangalli F., Remuzzi G., Benigni A. Analogs of bardoxolone methyl worsen diabetic nephropathy in rats with additional adverse effects. Am. J. Physiol. Renal. Physiol. 2013;304:F808–F819. doi: 10.1152/ajprenal.00376.2012.
    1. Fox R.J., Miller D.H., Phillips J.T., Hutchinson M., Havrdova E., Kita M., Yang M., Raghupathi K., Novas M., Sweetser M.T., et al. Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. N. Engl. J. Med. 2012;367:1087–1097. doi: 10.1056/NEJMoa1206328.
    1. Gold R., Kappos L., Arnold D.L., Bar-Or A., Giovannoni G., Selmaj K., Tornatore C., Sweetser M.T., Yang M., Sheikh S.I., et al. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N. Engl. J. Med. 2012;367:1098–1107. doi: 10.1056/NEJMoa1114287.
    1. Moreno J.A., Moreno S., Rubio-Navarro A., Sastre C., Blanco-Colio L.M., Gomez-Guerrero C., Ortiz A., Egido J. Targeting chemokines in proteinuria-induced renal disease. Expert Opin. Ther. Targets. 2012;16:833–845. doi: 10.1517/14728222.2012.703657.
    1. Sayyed S.G., Ryu M., Kulkarni O.P., Schmid H., Lichtnekert J., Gruner S., Green L., Mattei P., Hartmann G., Anders H.J. An orally active chemokine receptor CCR2 antagonist prevents glomerulosclerosis and renal failure in type 2 diabetes. Kidney Int. 2011;80:68–78. doi: 10.1038/ki.2011.102.
    1. Sullivan T., Miao Z., Dairaghi D.J., Krasinski A., Wang Y., Zhao B.N., Baumgart T., Ertl L.S., Pennell A., Seitz L., et al. CCR2 antagonist CCX140-B provides renal and glycemic benefits in diabetic transgenic human CCR2 knockin mice. Am. J. Physiol. Renal. Physiol. 2013;305:F1288–F1297. doi: 10.1152/ajprenal.00316.2013.
    1. Sullivan T.J., Miao Z., Zhao B.N., Ertl L.S., Wang Y., Krasinski A., Walters M.J., Powers J.P., Dairaghi D.J., Baumgart T., et al. Experimental evidence for the use of CCR2 antagonists in the treatment of type 2 diabetes. Metabolism. 2013;62:1623–1632. doi: 10.1016/j.metabol.2013.06.008.
    1. ChemoCentryx. [(accessed on 29 March 2015)]. Available online: .
    1. Blech M., Peter D., Fischer P., Bauer M.M., Hafner M., Zeeb M., Nar H. One target-two different binding modes: Structural insights into gevokizumab and canakinumab interactions to interleukin-1beta. J. Mol. Biol. 2013;425:94–111. doi: 10.1016/j.jmb.2012.09.021.
    1. Issafras H., Corbin J.A., Goldfine I.D., Roell M.K. Detailed mechanistic analysis of gevokizumab, an allosteric anti-IL-1beta antibody with differential receptor-modulating properties. J. Pharmacol. Exp. Ther. 2014;348:202–215. doi: 10.1124/jpet.113.205443.
    1. Reichert J.M. Antibodies to watch in 2015. MAbs. 2015;7:1–8. doi: 10.4161/19420862.2015.988944.
    1. European Union Clinical Trials Register. [(accessed on 29 March 2015)]. Available online: .
    1. Sanz A.B., Sanchez-Nino M.D., Ramos A.M., Moreno J.A., Santamaria B., Ruiz-Ortega M., Egido J., Ortiz A. NF-kappaB in renal inflammation. J. Am. Soc. Nephrol. 2010;21:1254–1262. doi: 10.1681/ASN.2010020218.
    1. Mora E., Guglielmotti A., Biondi G., Sassone-Corsi P. Bindarit: An anti-inflammatory small molecule that modulates the NFkappaB pathway. Cell Cycle. 2012;11:159–169. doi: 10.4161/cc.11.1.18559.
    1. Ble A., Mosca M., Di Loreto G., Guglielmotti A., Biondi G., Bombardieri S., Remuzzi G., Ruggenenti P. Antiproteinuric effect of chemokine C-C motif ligand 2 inhibition in subjects with acute proliferative lupus nephritis. Am. J. Nephrol. 2011;34:367–372. doi: 10.1159/000330685.
    1. Ruggenenti P. Effects of MCP-1 inhibition by bindarit therapy in type 2 diabetes subjects with micro- or macro-albuminuria. J. Am. Soc. Nephrol. 2010;21(Suppl. 1):44A.
    1. Berthier C.C., Zhang H., Schin M., Henger A., Nelson R.G., Yee B., Boucherot A., Neusser M.A., Cohen C.D., Carter-Su C., et al. Enhanced expression of Janus kinase-signal transducer and activator of transcription pathway members in human diabetic nephropathy. Diabetes. 2009;58:469–477. doi: 10.2337/db08-1328.
    1. Fernandez-Sanchez R., Berzal S., Sanchez-Nino M.D., Neria F., Goncalves S., Calabia O., Tejedor A., Calzada M.J., Caramelo C., Deudero J.J., et al. AG490 promotes HIF-1alpha accumulation by inhibiting its hydroxylation. Curr. Med. Chem. 2012;19:4014–4023. doi: 10.2174/092986712802002554.
    1. Miyata T., Suzuki N., van Ypersele de Strihou S.C. Diabetic nephropathy: Are there new and potentially promising therapies targeting oxygen biology? Kidney Int. 2013;84:693–702. doi: 10.1038/ki.2013.74.
    1. Banes A.K., Shaw S., Jenkins J., Redd H., Amiri F., Pollock D.M., Marrero M.B. Angiotensin II blockade prevents hyperglycemia-induced activation of JAK and STAT proteins in diabetic rat kidney glomeruli. Am. J. Physiol. Renal Physiol. 2004;286:F653–F659. doi: 10.1152/ajprenal.00163.2003.
    1. Taira M., Inaba M., Takada K., Baba S., Fukui J., Ueda Y., Kwon A.H., Hisha H., Kamiyama Y., Ikehara S. Treatment of streptozotocin-induced diabetes mellitus in rats by transplantation of islet cells from two major histocompatibility complex disparate rats in combination with intra bone marrow injection of allogeneic bone marrow cells. Transplantation. 2005;79:680–687. doi: 10.1097/01.TP.0000155500.17348.94.
    1. Ortiz-Munoz G., Lopez-Parra V., Lopez-Franco O., Fernandez-Vizarra P., Mallavia B., Flores C., Sanz A., Blanco J., Mezzano S., Ortiz A., et al. Suppressors of cytokine signaling abrogate diabetic nephropathy. J. Am. Soc. Nephrol. 2010;21:763–772. doi: 10.1681/ASN.2009060625.
    1. Taylor P., Genovese M., Keystone E., Schlichting D., Beattie S., Macias W. Baricitinib, an oraljanus kinase inhibitor, in the treatment of rheumatoid arthritis: Safety and efficacy in an open-label, long-term extension study. Ann. Rheum. Dis. 2014;73 doi: 10.1136/annrheumdis-2013-205124.71.
    1. Dang Z., MacKinnon A., Marson L.P., Sethi T. Tubular atrophy and interstitial fibrosis after renal transplantation is dependent on galectin-3. Transplantation. 2012;93:477–484. doi: 10.1097/TP.0b013e318242f40a.
    1. de Boer R.A., Lok D.J., Jaarsma T., van der Meer P., Voors A.A., Hillege H.L., van Veldhuisen D.J. Predictive value of plasma galectin-3 levels in heart failure with reduced and preserved ejection fraction. Ann. Med. 2011;43:60–68. doi: 10.3109/07853890.2010.538080.
    1. Fernandes Bertocchi A.P., Campanhole G., Wang P.H., Goncalves G.M., Damiao M.J., Cenedeze M.A., Beraldo F.C., de Paula A.T., Dos Reis M.A., Mazzali M., et al. A Role for galectin-3 in renal tissue damage triggered by ischemia and reperfusion injury. Transpl. Int. 2008;21:999–1007. doi: 10.1111/j.1432-2277.2008.00705.x.
    1. Henderson N.C., Mackinnon A.C., Farnworth S.L., Kipari T., Haslett C., Iredale J.P., Liu F.T., Hughes J., Sethi T. Galectin-3 expression and secretion links macrophages to the promotion of renal fibrosis. Am. J. Pathol. 2008;172:288–298. doi: 10.2353/ajpath.2008.070726.
    1. Karpf R.J. Effects of emotions on altruism and social inference in retarded adolescents. Psychol. Rep. 1977;41:135–138. doi: 10.2466/pr0.1977.41.1.135.
    1. Kikuchi Y., Kobayashi S., Hemmi N., Ikee R., Hyodo N., Saigusa T., Namikoshi T., Yamada M., Suzuki S., Miura S. Galectin-3-positive cell infiltration in human diabetic nephropathy. Nephrol. Dial. Transplant. 2004;19:602–607. doi: 10.1093/ndt/gfg603.
    1. Drechsler C., Delgado G., Wanner C., Blouin K., Pilz S., Tomaschitz A., Kleber M.E., Dressel A., Willmes C., Krane V., et al. Galectin-3, renal function, and clinical outcomes: Results from the LURIC and 4D Studies. J. Am. Soc. Nephrol. 2015 doi: 10.1681/ASN.2014010093.
    1. Iacobini C., Oddi G., Menini S., Amadio L., Ricci C., Di Pippo C., Sorcini M., Pricci F., Pugliese F., Pugliese G. Development of age-dependent glomerular lesions in galectin-3/AGE-receptor-3 knockout mice. Am. J. Physiol. Renal Physiol. 2005;289:F611–F621. doi: 10.1152/ajprenal.00435.2004.
    1. Pugliese G., Pricci F., Iacobini C., Leto G., Amadio L., Barsotti P., Frigeri L., Hsu D.K., Vlassara H., Liu F.T., et al. Accelerated diabetic glomerulopathy in galectin-3/AGE receptor 3 knockout mice. FASEB J. 2001;15:2471–2479. doi: 10.1096/fj.01-0006com.
    1. Sachs N., Sonnenberg A. Cell-matrix adhesion of podocytes in physiology and disease. Nat. Rev. Nephrol. 2013;9:200–210. doi: 10.1038/nrneph.2012.291.
    1. Yoon S., Gingras D., Bendayan M. Alterations of vitronectin and its receptor alpha(v) integrin in the rat renal glomerular wall during diabetes. Am. J. Kidney Dis. 2001;38:1298–1306. doi: 10.1053/ajkd.2001.29228.
    1. Yoo T.H., Pedigo C.E., Guzman J., Correa-Medina M., Wei C., Villarreal R., Mitrofanova A., Leclercq F., Faul C., Li J., et al. Sphingomyelinase-like phosphodiesterase 3b expression levels determine podocyte injury phenotypes in glomerular disease. J. Am. Soc. Nephrol. 2015;26:133–147. doi: 10.1681/ASN.2013111213.
    1. Maile L.A., Busby W.H., Gollahon K.A., Flowers W., Garbacik N., Garbacik S., Stewart K., Nichols T., Bellinger D., Patel A., et al. Blocking ligand occupancy of the αVβ3 integrin inhibits the development of nephropathy in diabetic pigs. Endocrinology. 2014;155:4665–4675. doi: 10.1210/en.2014-1318.
    1. Hattori K., Naguro I., Runchel C., Ichijo H. The roles of ASK family proteins in stress responses and diseases. Cell Commun. Signal. 2009;7 doi: 10.1186/1478-811X-7-9.
    1. Kawarazaki Y., Ichijo H., Naguro I. Apoptosis signal-regulating kinase 1 as a therapeutic target. Expert Opin. Ther. Targets. 2014;18:651–664. doi: 10.1517/14728222.2014.896903.
    1. Wang F., Wu Y., Gu H., Reece E.A., Fang S., Gabbay-Benziv R., Aberdeen G., Yang P. Ask1 gene deletion blocks maternal diabetes-induced endoplasmic reticulum stress in the developing embryo by disrupting the unfolded protein response signalosome. Diabetes. 2015;64:973–988. doi: 10.2337/db14-0409.
    1. Yokoi T., Fukuo K., Yasuda O., Hotta M., Miyazaki J., Takemura Y., Kawamoto H., Ichijo H., Ogihara T. Apoptosis signal-regulating kinase 1 mediates cellular senescence induced by high glucose in endothelial cells. Diabetes. 2006;55:1660–1665. doi: 10.2337/db05-1607.
    1. Yamaguchi K., Takeda K., Kadowaki H., Ueda I., Namba Y., Ouchi Y., Nishitoh H., Ichijo H. Involvement of ASK1-p38 pathway in the pathogenesis of diabetes triggered by pancreatic β cell exhaustion. Biochim. Biophys. Acta. 2013;1830:3656–3663. doi: 10.1016/j.bbagen.2013.01.029.

Source: PubMed

Спонсоры и соавторы

Заболевания

Медикаментозные вмешательства

Подписаться