Abstract
Autosomal Dominant Polycystic Kidney Disease (ADPKD), the most common monogenic kidney disease, is caused by mutations in the PKD1, PKD2 or, in a very limited number of families, GANAB genes. Although cellular and molecular mechanisms of this disease have been understood in the past 20 years, specific therapy approaches remain very little. Both experimental and clinical studies show that the mammalian or mechanistic target of rapamycin (mTOR) pathway plays an important role during cyst formation and enlargement in ADPKD. Studies in rodent models of ADPKD showed that mTOR inhibitors had a significant and long-lasting decrease in kidney volume and amelioration in kidney function. In the past over ten years, researchers have been devoting continuously to test mTOR inhibitors efficacy and safety in both preclinical studies and clinical trials in patients with ADPKD. In this review, we will discuss the mTOR pathway thoroughly, mainly focusing on current advances in understanding its role in ADPKD, especially the recent progress of mTOR inhibitors use in preclinical studies and clinical trials.
Keywords: Autosomal dominant polycystic kidney disease, mTOR Signaling, mTOR inhibitors, efficacy and safety, preclinical models, clinical trials.
[1]
Harris, P.C.; Torres, V.E. Polycystic kidney disease. Annu. Rev. Med., 2009, 60, 321-337. [http://dx.doi.org/10.1146/annurev.med.60.101707.125712]. [PMID: 18947299].
[2]
Torres, V.E.; Harris, P.C. Autosomal dominant polycystic kidney disease: the last 3 years. Kidney Int., 2009, 76(2), 149-168. [http://dx.doi.org/10.1038/ki.2009.128]. [PMID: 19455193].
[3]
Ecder, T.; Schrier, R.W. Cardiovascular abnormalities in autosomal-dominant polycystic kidney disease. Nat. Rev. Nephrol., 2009, 5(4), 221-228. [http://dx.doi.org/10.1038/nrneph.2009.13]. [PMID: 19322187].
[4]
Sweeney, W.E., Jr; Avner, E.D. Diagnosis and management of childhood polycystic kidney disease. Pediatr. Nephrol., 2011, 26(5), 675-692. [http://dx.doi.org/10.1007/s00467-010-1656-1]. [PMID: 21046169].
[5]
Menezes, L.F.; Onuchic, L.F. Molecular and cellular pathogenesis of autosomal recessive polycystic kidney disease. Braz. J. Med. Biol. Res., 2006, 39(12), 1537-1548. [http://dx.doi.org/10.1590/S0100-879X2006001200004]. [PMID: 17160262].
[6]
Hildebrandt, F.; Attanasio, M.; Otto, E. Nephronophthisis: Disease mechanisms of a ciliopathy. J. Am. Soc. Nephrol., 2009, 20(1), 23-35. [http://dx.doi.org/10.1681/ASN.2008050456]. [PMID: 19118152].
[7]
Ibraghimov-Beskrovnaya, O.; Natoli, T.A. mTOR signaling in polycystic kidney disease. Trends Mol. Med., 2011, 17(11), 625-633. [http://dx.doi.org/10.1016/j.molmed.2011.06.003]. [PMID: 21775207].
[8]
Braun, W.E. Autosomal dominant polycystic kidney disease: emerging concepts of pathogenesis and new treatments. Cleve. Clin. J. Med., 2009, 76(2), 97-104. [http://dx.doi.org/10.3949/ccjm.76a.gr001]. [PMID: 19188475].
[9]
Kim, H.J.; Edelstein, C.L. Mammalian target of rapamycin inhibition in polycystic kidney disease: From bench to bedside. Kidney Res. Clin. Pract., 2012, 31(3), 132-138. [http://dx.doi.org/10.1016/j.krcp.2012.07.002]. [PMID: 26894018].
[10]
Gabow, P.A. Autosomal dominant polycystic kidney disease. N. Engl. J. Med., 1993, 329(5), 332-342. [http://dx.doi.org/10.1056/NEJM199307293290508]. [PMID: 8321262].
[11]
Torres, V.E. Treatment strategies and clinical trial design in ADPKD. Adv. Chronic Kidney Dis., 2010, 17(2), 190-204. [http://dx.doi.org/10.1053/j.ackd.2010.01.006]. [PMID: 20219622].
[12]
Torres, V.E.; Harris, P.C.; Pirson, Y. Autosomal dominant polycystic kidney disease. Lancet, 2007, 369(9569), 1287-1301. [http://dx.doi.org/10.1016/S0140-6736(07)60601-1]. [PMID: 17434405].
[13]
Venkatachalam, K.; Montell, C. TRP channels. Annu. Rev. Biochem., 2007, 76, 387-417. [http://dx.doi.org/10.1146/annurev.biochem.75.103004.142819]. [PMID: 17579562].
[14]
Porath, B.; Gainullin, V.G.; Cornec-Le Gall, E.; Dillinger, E.K.; Heyer, C.M.; Hopp, K.; Edwards, M.E.; Madsen, C.D.; Mauritz, S.R.; Banks, C.J.; Baheti, S.; Reddy, B.; Herrero, J.I.; Bañales, J.M.; Hogan, M.C.; Tasic, V.; Watnick, T.J.; Chapman, A.B.; Vigneau, C.; Lavainne, F.; Audrézet, M.P.; Ferec, C.; Le Meur, Y.; Torres, V.E.; Harris, P.C. Mutations in GANAB, encoding the glucosidase IIα subunit, cause autosomal-dominant polycystic kidney and liver disease. Am. J. Hum. Genet., 2016, 98(6), 1193-1207. [http://dx.doi.org/10.1016/j.ajhg.2016.05.004]. [PMID: 27259053].
[15]
Brook-Carter, P.T.; Peral, B.; Ward, C.J.; Thompson, P.; Hughes, J.; Maheshwar, M.M.; Nellist, M.; Gamble, V.; Harris, P.C.; Sampson, J.R. Deletion of the TSC2 and PKD1 genes associated with severe infantile polycystic kidney disease-a contiguous gene syndrome. Nat. Genet., 1994, 8(4), 328-332. [http://dx.doi.org/10.1038/ng1294-328]. [PMID: 7894481].
[16]
Gingras, A.C.; Raught, B.; Sonenberg, N. Regulation of translation initiation by FRAP/mTOR. Genes Dev., 2001, 15(7), 807-826. [http://dx.doi.org/10.1101/gad.887201]. [PMID: 11297505].
[17]
Yip, C.K.; Murata, K.; Walz, T.; Sabatini, D.M.; Kang, S.A. Structure of the human mTOR complex I and its implications for rapamycin inhibition. Mol. Cell, 2010, 38(5), 768-774. [http://dx.doi.org/10.1016/j.molcel.2010.05.017]. [PMID: 20542007].
[18]
Peterson, T.R.; Laplante, M.; Thoreen, C.C.; Sancak, Y.; Kang, S.A.; Kuehl, W.M.; Gray, N.S.; Sabatini, D.M. DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival. Cell, 2009, 137(5), 873-886. [http://dx.doi.org/10.1016/j.cell.2009.03.046]. [PMID: 19446321].
[19]
Jacinto, E.; Loewith, R.; Schmidt, A.; Lin, S.; Rüegg, M.A.; Hall, A.; Hall, M.N. Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat. Cell Biol., 2004, 6(11), 1122-1128. [http://dx.doi.org/10.1038/ncb1183]. [PMID: 15467718].
[20]
Sarbassov, D.D.; Ali, S.M.; Kim, D.H.; Guertin, D.A.; Latek, R.R.; Erdjument-Bromage, H.; Tempst, P.; Sabatini, D.M. Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr. Biol., 2004, 14(14), 1296-1302. [http://dx.doi.org/10.1016/j.cub.2004.06.054]. [PMID: 15268862].
[21]
Wullschleger, S.; Loewith, R.; Hall, M.N. TOR signaling in growth and metabolism. Cell, 2006, 124(3), 471-484. [http://dx.doi.org/10.1016/j.cell.2006.01.016]. [PMID: 16469695].
[22]
Kim, D.H.; Sarbassov, D.D.; Ali, S.M.; King, J.E.; Latek, R.R.; Erdjument-Bromage, H.; Tempst, P.; Sabatini, D.M. mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell, 2002, 110(2), 163-175. [http://dx.doi.org/10.1016/S0092-8674(02)00808-5]. [PMID: 12150925].
[23]
Sarbassov, D.D.; Guertin, D.A.; Ali, S.M.; Sabatini, D.M. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science, 2005, 307(5712), 1098-1101. [http://dx.doi.org/10.1126/science.1106148]. [PMID: 15718470].
[24]
Fantus, D.; Rogers, N.M.; Grahammer, F.; Huber, T.B.; Thomson, A.W. Roles of mTOR complexes in the kidney: implications for renal disease and transplantation. Nat. Rev. Nephrol., 2016, 12(10), 587-609. [http://dx.doi.org/10.1038/nrneph.2016.108]. [PMID: 27477490].
[25]
Bonnet, C.S.; Aldred, M.; von Ruhland, C.; Harris, R.; Sandford, R.; Cheadle, J.P. Defects in cell polarity underlie TSC and ADPKD-associated cystogenesis. Hum. Mol. Genet., 2009, 18(12), 2166-2176. [http://dx.doi.org/10.1093/hmg/ddp149]. [PMID: 19321600].
[26]
Cai, S.L.; Walker, C.L. TSC2, a key player in tumor suppression and cystic kidney disease. Nephrol. Ther., 2006, 2(Suppl. 2), S119-S122. [PMID: 17373211].
[27]
Kleymenova, E.; Ibraghimov-Beskrovnaya, O.; Kugoh, H.; Everitt, J.; Xu, H.; Kiguchi, K.; Landes, G.; Harris, P.; Walker, C. Tuberin-dependent membrane localization of polycystin-1: A functional link between polycystic kidney disease and the TSC2 tumor suppressor gene. Mol. Cell, 2001, 7(4), 823-832. [http://dx.doi.org/10.1016/S1097-2765(01)00226-X]. [PMID: 11336705].
[28]
Canaud, G.; Knebelmann, B.; Harris, P.C.; Vrtovsnik, F.; Correas, J.M.; Pallet, N.; Heyer, C.M.; Letavernier, E.; Bienaimé, F.; Thervet, E.; Martinez, F.; Terzi, F.; Legendre, C. Therapeutic mTOR inhibition in autosomal dominant polycystic kidney disease: What is the appropriate serum level? Am. J. Transplant., 2010, 10(7), 1701-1706. [http://dx.doi.org/10.1111/j.1600-6143.2010.03152.x]. [PMID: 20642692].
[29]
Shillingford, J.M.; Murcia, N.S.; Larson, C.H.; Low, S.H.; Hedgepeth, R.; Brown, N.; Flask, C.A.; Novick, A.C.; Goldfarb, D.A.; Kramer-Zucker, A.; Walz, G.; Piontek, K.B.; Germino, G.G.; Weimbs, T. The mTOR pathway is regulated by polycystin-1, and its inhibition reverses renal cystogenesis in polycystic kidney disease. Proc. Natl. Acad. Sci. USA, 2006, 103(14), 5466-5471. [http://dx.doi.org/10.1073/pnas.0509694103]. [PMID: 16567633].
[30]
Zafar, I.; Ravichandran, K.; Belibi, F.A.; Doctor, R.B.; Edelstein, C.L. Sirolimus attenuates disease progression in an orthologous mouse model of human autosomal dominant polycystic kidney disease. Kidney Int., 2010, 78(8), 754-761. [http://dx.doi.org/10.1038/ki.2010.250]. [PMID: 20686448].
[31]
Gattone, V.H., II; Sinders, R.M.; Hornberger, T.A.; Robling, A.G. Late progression of renal pathology and cyst enlargement is reduced by rapamycin in a mouse model of nephronophthisis. Kidney Int., 2009, 76(2), 178-182. [http://dx.doi.org/10.1038/ki.2009.147]. [PMID: 19421190].
[32]
Natoli, T.A.; Smith, L.A.; Rogers, K.A.; Wang, B.; Komarnitsky, S.; Budman, Y.; Belenky, A.; Bukanov, N.O.; Dackowski, W.R.; Husson, H.; Russo, R.J.; Shayman, J.A.; Ledbetter, S.R.; Leonard, J.P.; Ibraghimov-Beskrovnaya, O. Inhibition of glucosylceramide accumulation results in effective blockade of polycystic kidney disease in mouse models. Nat. Med., 2010, 16(7), 788-792. [http://dx.doi.org/10.1038/nm.2171]. [PMID: 20562878].
[33]
Hartman, T.R.; Liu, D.; Zilfou, J.T.; Robb, V.; Morrison, T.; Watnick, T.; Henske, E.P. The tuberous sclerosis proteins regulate formation of the primary cilium via a rapamycin-insensitive and polycystin 1-independent pathway. Hum. Mol. Genet., 2009, 18(1), 151-163. [http://dx.doi.org/10.1093/hmg/ddn325]. [PMID: 18845692].
[34]
Foster, D.A.; Toschi, A. Targeting mTOR with rapamycin: one dose does not fit all. Cell Cycle, 2009, 8(7), 1026-1029. [http://dx.doi.org/10.4161/cc.8.7.8044]. [PMID: 19270529].
[35]
Cook, J.A.; Oliver, K.; Mueller, R.F.; Sampson, J. A cross sectional study of renal involvement in tuberous sclerosis. J. Med. Genet., 1996, 33(6), 480-484. [http://dx.doi.org/10.1136/jmg.33.6.480]. [PMID: 8782048].
[36]
Benjamin, D.; Colombi, M.; Moroni, C.; Hall, M.N. Rapamycin passes the torch: A new generation of mTOR inhibitors. Nat. Rev. Drug Discov., 2011, 10(11), 868-880. [http://dx.doi.org/10.1038/nrd3531]. [PMID: 22037041].
[37]
Faivre, S.; Kroemer, G.; Raymond, E. Current development of mTOR inhibitors as anticancer agents. Nat. Rev. Drug Discov., 2006, 5(8), 671-688. [http://dx.doi.org/10.1038/nrd2062]. [PMID: 16883305].
[38]
Toschi, A.; Lee, E.; Xu, L.; Garcia, A.; Gadir, N.; Foster, D.A. Regulation of mTORC1 and mTORC2 complex assembly by phosphatidic acid: Competition with rapamycin. Mol. Cell. Biol., 2009, 29(6), 1411-1420. [http://dx.doi.org/10.1128/MCB.00782-08]. [PMID: 19114562].
[39]
Shillingford, J.M.; Piontek, K.B.; Germino, G.G.; Weimbs, T. Rapamycin ameliorates PKD resulting from conditional inactivation of Pkd1. J. Am. Soc. Nephrol., 2010, 21(3), 489-497. [http://dx.doi.org/10.1681/ASN.2009040421]. [PMID: 20075061].
[40]
Reichardt, W.; Romaker, D.; Becker, A.; Buechert, M.; Walz, G.; von Elverfeldt, D. Monitoring kidney and renal cyst volumes applying MR approaches on a rapamycin treated mouse model of ADPKD. MAGMA, 2009, 22(3), 143-149. [http://dx.doi.org/10.1007/s10334-008-0158-7]. [PMID: 19107537].
[41]
Tao, Y.; Kim, J.; Schrier, R.W.; Edelstein, C.L. Rapamycin markedly slows disease progression in a rat model of polycystic kidney disease. J. Am. Soc. Nephrol., 2005, 16(1), 46-51. [http://dx.doi.org/10.1681/ASN.2004080660]. [PMID: 15563559].
[42]
Wahl, P.R.; Serra, A.L.; Le Hir, M.; Molle, K.D.; Hall, M.N.; Wüthrich, R.P. Inhibition of mTOR with sirolimus slows disease progression in Han:SPRD rats with Autosomal Dominant Polycystic Kidney Disease (ADPKD). Nephrol. Dial. Transplant., 2006, 21(3), 598-604. [http://dx.doi.org/10.1093/ndt/gfi181]. [PMID: 16221708].
[43]
Renken, C.; Fischer, D.C.; Kundt, G.; Gretz, N.; Haffner, D. Inhibition of mTOR with sirolimus does not attenuate progression of liver and kidney disease in PCK rats. Nephrol. Dial. Transplant., 2011, 26(1), 92-100. [http://dx.doi.org/10.1093/ndt/gfq384]. [PMID: 20615907].
[44]
Belibi, F.; Ravichandran, K.; Zafar, I.; He, Z.; Edelstein, C.L. mTORC1/2 and rapamycin in female Han:SPRD rats with polycystic kidney disease. Am. J. Physiol. Renal Physiol., 2011, 300(1), F236-F244. [http://dx.doi.org/10.1152/ajprenal.00129.2010]. [PMID: 20943770].
[45]
Pema, M.; Drusian, L.; Chiaravalli, M.; Castelli, M.; Yao, Q.; Ricciardi, S.; Somlo, S.; Qian, F.; Biffo, S.; Boletta, A. mTORC1-mediated inhibition of polycystin-1 expression drives renal cyst formation in tuberous sclerosis complex. Nat. Commun., 2016, 7, 10786. [http://dx.doi.org/10.1038/ncomms10786]. [PMID: 26931735].
[46]
Wu, M.; Arcaro, A.; Varga, Z.; Vogetseder, A.; Le Hir, M.; Wüthrich, R.P.; Serra, A.L. Pulse mTOR inhibitor treatment effectively controls cyst growth but leads to severe parenchymal and glomerular hypertrophy in rat polycystic kidney disease. Am. J. Physiol. Renal Physiol., 2009, 297(6), F1597-F1605. [http://dx.doi.org/10.1152/ajprenal.00430.2009]. [PMID: 19776171].
[47]
Wu, M.; Wahl, P.R.; Le Hir, M.; Wackerle-Men, Y.; Wuthrich, R.P.; Serra, A.L. Everolimus retards cyst growth and preserves kidney function in a rodent model for polycystic kidney disease. Kidney Blood Press. Res., 2007, 30(4), 253-259. [http://dx.doi.org/10.1159/000104818]. [PMID: 17596700].
[48]
Grantham, J.J.; Torres, V.E.; Chapman, A.B.; Guay-Woodford, L.M.; Bae, K.T.; King, B.F., Jr; Wetzel, L.H.; Baumgarten, D.A.; Kenney, P.J.; Harris, P.C.; Klahr, S.; Bennett, W.M.; Hirschman, G.N.; Meyers, C.M.; Zhang, X.; Zhu, F.; Miller, J.P. Volume progression in polycystic kidney disease. N. Engl. J. Med., 2006, 354(20), 2122-2130. [http://dx.doi.org/10.1056/NEJMoa054341]. [PMID: 16707749].
[49]
Torres, V.E.; Boletta, A.; Chapman, A.; Gattone, V.; Pei, Y.; Qian, Q.; Wallace, D.P.; Weimbs, T.; Wüthrich, R.P. Prospects for mTOR inhibitor use in patients with polycystic kidney disease and hamartomatous diseases. Clin. J. Am. Soc. Nephrol., 2010, 5(7), 1312-1329. [http://dx.doi.org/10.2215/CJN.01360210]. [PMID: 20498248].
[50]
Qian, Q.; Du, H.; King, B.F.; Kumar, S.; Dean, P.G.; Cosio, F.G.; Torres, V.E. Sirolimus reduces polycystic liver volume in ADPKD patients. J. Am. Soc. Nephrol., 2008, 19(3), 631-638. [http://dx.doi.org/10.1681/ASN.2007050626]. [PMID: 18199797].
[51]
Serra, A.L.; Poster, D.; Kistler, A.D.; Krauer, F.; Raina, S.; Young, J.; Rentsch, K.M.; Spanaus, K.S.; Senn, O.; Kristanto, P.; Scheffel, H.; Weishaupt, D.; Wüthrich, R.P. Sirolimus and kidney growth in autosomal dominant polycystic kidney disease. N. Engl. J. Med., 2010, 363(9), 820-829. [http://dx.doi.org/10.1056/NEJMoa0907419]. [PMID: 20581391].
[52]
Walz, G.; Budde, K.; Mannaa, M.; Nürnberger, J.; Wanner, C.; Sommerer, C.; Kunzendorf, U.; Banas, B.; Hörl, W.H.; Obermüller, N.; Arns, W.; Pavenstädt, H.; Gaedeke, J.; Büchert, M.; May, C.; Gschaidmeier, H.; Kramer, S.; Eckardt, K.U. Everolimus in patients with autosomal dominant polycystic kidney disease. N. Engl. J. Med., 2010, 363(9), 830-840. [http://dx.doi.org/10.1056/NEJMoa1003491]. [PMID: 20581392].
[53]
Huber, T.B.; Walz, G.; Kuehn, E.W. mTOR and rapamycin in the kidney: Signaling and therapeutic implications beyond immunosuppression. Kidney Int., 2011, 79(5), 502-511. [http://dx.doi.org/10.1038/ki.2010.457]. [PMID: 21085109].
[54]
Perico, N.; Antiga, L.; Caroli, A.; Ruggenenti, P.; Fasolini, G.; Cafaro, M.; Ondei, P.; Rubis, N.; Diadei, O.; Gherardi, G.; Prandini, S.; Panozo, A.; Bravo, R.F.; Carminati, S.; De Leon, F.R.; Gaspari, F.; Cortinovis, M.; Motterlini, N.; Ene-Iordache, B.; Remuzzi, A.; Remuzzi, G. Sirolimus therapy to halt the progression of ADPKD. J. Am. Soc. Nephrol., 2010, 21(6), 1031-1040. [http://dx.doi.org/10.1681/ASN.2009121302]. [PMID: 20466742].
[55]
Ponticelli, C.; Locatelli, F. Autosomal dominant polycystic kidney disease and mTOR inhibitors: the narrow road between hope and disappointment. Nephrol. Dial. Transplant., 2010, 25(12), 3809-3812. [http://dx.doi.org/10.1093/ndt/gfq527]. [PMID: 20798121].
[56]
Roychowdhury, A.; Sharma, R.; Kumar, S. Recent advances in the discovery of small molecule mTOR inhibitors. Future Med. Chem., 2010, 2(10), 1577-1589. [http://dx.doi.org/10.4155/fmc.10.233]. [PMID: 21426150].
[57]
Head, S.A.; Shi, W.Q.; Yang, E.J.; Nacev, B.A.; Hong, S.Y.; Pasunooti, K.K.; Li, R.J.; Shim, J.S.; Liu, J.O. Simultaneous Targeting of NPC1 and VDAC1 by Itraconazole Leads to Synergistic Inhibition of mTOR Signaling and Angiogenesis. ACS Chem. Biol., 2017, 12(1), 174-182. [http://dx.doi.org/10.1021/acschembio.6b00849]. [PMID: 28103683].
[58]
McCarty, M.F.; Barroso-Aranda, J.; Contreras, F. Activation of AMP-activated kinase as a strategy for managing autosomal dominant polycystic kidney disease. Med. Hypotheses, 2009, 73(6), 1008-1010. [http://dx.doi.org/10.1016/j.mehy.2009.05.043]. [PMID: 19570618].
[59]
Takiar, V.; Nishio, S.; Seo-Mayer, P.; King, J.D., Jr; Li, H.; Zhang, L.; Karihaloo, A.; Hallows, K.R.; Somlo, S.; Caplan, M.J. Activating AMP-Activated Protein Kinase (AMPK) slows renal cystogenesis. Proc. Natl. Acad. Sci. USA, 2011, 108(6), 2462-2467. [http://dx.doi.org/10.1073/pnas.1011498108]. [PMID: 21262823].
[60]
Ruggenenti, P.; Gentile, G.; Perico, N.; Perna, A.; Barcella, L.; Trillini, M.; Cortinovis, M.; Ferrer Siles, C.P.; Reyes Loaeza, J.A.; Aparicio, M.C.; Fasolini, G.; Gaspari, F.; Martinetti, D.; Carrara, F.; Rubis, N.; Prandini, S.; Caroli, A.; Sharma, K.; Antiga, L.; Remuzzi, A.; Remuzzi, G. Effect of sirolimus on disease progression in patients with autosomal dominant polycystic kidney disease and CKD stages 3b-4. Clin. J. Am. Soc. Nephrol., 2016, 11(5), 785-794. [http://dx.doi.org/10.2215/CJN.09900915]. [PMID: 26912555].
[61]
Xue, C.; Dai, B.; Mei, C. Long-term treatment with mammalian target of rapamycin inhibitor does not benefit patients with autosomal dominant polycystic kidney disease: a meta-analysis. Nephron Clin. Pract., 2013, 124(1-2), 10-16. [http://dx.doi.org/10.1159/000354398]. [PMID: 24022660].
[62]
Shillingford, J.M.; Leamon, C.P.; Vlahov, I.R.; Weimbs, T. Folate-conjugated rapamycin slows progression of polycystic kidney disease. J. Am. Soc. Nephrol., 2012, 23(10), 1674-1681. [http://dx.doi.org/10.1681/ASN.2012040367]. [PMID: 22859856].
[63]
Riegersperger, M.; Herkner, H.; Sunder-Plassmann, G. Pulsed oral sirolimus in advanced autosomal-dominant polycystic kidney disease (Vienna RAP Study): Study protocol for a randomized controlled trial. Trials, 2015, 16, 182. [http://dx.doi.org/10.1186/s13063-015-0692-3]. [PMID: 25899445].
[64]
Braun, W.E.; Schold, J.D.; Stephany, B.R.; Spirko, R.A.; Herts, B.R. Low-dose rapamycin (sirolimus) effects in autosomal dominant polycystic kidney disease: an open-label randomized controlled pilot study. Clin. J. Am. Soc. Nephrol., 2014, 9(5), 881-888. [http://dx.doi.org/10.2215/CJN.02650313]. [PMID: 24721888].
Related Journals
Current Pharmaceutical Design
Current Topics in Medicinal Chemistry
Current Respiratory Medicine Reviews
Infectious Disorders - Drug Targets
Endocrine, Metabolic & Immune Disorders - Drug Targets
Anti-Infective Agents
Coronaviruses
Recent Advances in Inflammation & Allergy Drug Discovery
Current Probiotics
Article Metrics
68
17
2
1