Metformina e rene policistico dell’adulto: tra ricerca e impiego clinico

Autori

  • Giovanni Piscopo Nefrologia, Dialisi e Trapianto, AOUC Policlinico di Bari - Italy

DOI:

https://doi.org/10.33393/gcnd.2022.2398

Parole chiave:

Autosomal Dominal Polycystic Kidney Disease (ADPKD), Cyst formation, Metformin, Renal tissue damage

Abstract

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common monogenic nephropathy. It is characterized by the onset of progressively enlarging cysts in kidneys (and in other organs, mainly in the liver) that cause the progressive deterioration of renal function.

Since 2018, Tolvaptan is available for the treatment of the disease (and in Italy also Octreotide), and allows to slow the progression of the disease towards renal failure. This new drug, even representing an epochal revolution in the management of this pathology, is not without side effects as well as potential adverse events that, although rare, should not be neglected (so much so as to make it necessary to monitor, first monthly and then quarterly, some important bio-humoral parameters).

Therefore, the war for the defeat of ADPKD is far from being won and new efforts are needed to increase knowledge about the complex pathophysiology of this disease in order to identify other candidate molecules for the treatment of the disease.

Among these Metformin, a drug that has long been used in the treatment of type 2 diabetes mellitus, according to numerous preclinical and clinical studies, would be able to reduce the development and formation of cysts, with a slowdown in the tissue damage related to them and of the progression to end-stage renal failure.

Riferimenti bibliografici

Torres VE, Harris PC, Pirson Y. Autosomal dominant polycystic kidney disease. Lancet. 2007;369(9569):1287-1301. https://doi.org/10.1016/S0140-6736(07)60601-1PMID:17434405 DOI: https://doi.org/10.1016/S0140-6736(07)60601-1

Torra Balcells R, Ars Criach E. Molecular diagnosis of autosomal dominant polycystic kidney disease. Nefrologia. 2011;31(1):35-43. https://doi.org/10.3265/Nefrologia.pre2010.Nov.10727 PMID:21270911

Ong AC, Harris PC. Molecular pathogenesis of ADPKD: the polycystin complex gets complex. Kidney Int. 2005;67(4):1234-1247. https://doi.org/10.1111/j.1523-1755.2005.00201.x PMID:15780076 DOI: https://doi.org/10.1111/j.1523-1755.2005.00201.x

Gattone VH II, Wang X, Harris PC, Torres VE. Inhibition of renal cystic disease development and progression by a vasopressin V2 receptor antagonist. Nat Med. 2003;9(10):1323-1326. https://doi.org/10.1038/nm935 PMID:14502283 DOI: https://doi.org/10.1038/nm935

Perico N, Ruggenenti P, Perna A, et al; ALADIN 2 Study Group. Octreotide-LAR in later-stage autosomal dominant polycystic kidney disease (ALADIN 2): A randomized, double-blind, placebo-controlled, multicenter trial. PLoS Med. 2019;16(4):e1002777. https://doi.org/10.1371/journal.pmed.1002777 PMID:30951521 DOI: https://doi.org/10.1371/journal.pmed.1002777

Shillingford JM, Murcia NS, Larson CH, et al. 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. https://doi.org/10.1073/pnas.0509694103PMID:16567633 DOI: https://doi.org/10.1073/pnas.0509694103

Serra AL, Poster D, Kistler AD, et al. Sirolimus and kidney growth in autosomal dominant polycystic kidney disease. N Engl J Med. 2010;363(9):820-829. https://doi.org/10.1056/NEJMoa0907419 PMID:20581391 DOI: https://doi.org/10.1056/NEJMoa0907419

Walz G, Budde K, Mannaa M, et al. Everolimus in patients with autosomal dominant polycystic kidney disease. N Engl J Med. 2010;363(9):830-840. https://doi.org/10.1056/NEJMoa1003491PMID:20581392 DOI: https://doi.org/10.1056/NEJMoa1003491

Steinberg GR, Carling D. AMP-activated protein kinase: the current landscape for drug development. Nat Rev Drug Discov. 2019;18(7):527-551. https://doi.org/10.1038/s41573-019-0019-2 PMID:30867601 DOI: https://doi.org/10.1038/s41573-019-0019-2

Rajani R, Pastor-Soler NM, Hallows KR. Role of AMP-activated protein kinase in kidney tubular transport, metabolism, and disease. Curr Opin Nephrol Hypertens. 2017;26(5):375-383. https://doi.org/10.1097/MNH.0000000000000349 PMID:28614117 DOI: https://doi.org/10.1097/MNH.0000000000000349

Declèves AE, Mathew AV, Cunard R, Sharma K. AMPK mediates the initiation of kidney disease induced by a high-fat diet. J Am Soc Nephrol. 2011;22(10):1846-1855. https://doi.org/10.1681/ASN.2011010026 PMID:21921143 DOI: https://doi.org/10.1681/ASN.2011010026

Peairs A, Radjavi A, Davis S, et al. Activation of AMPK inhibits inflammation in MRL/lpr mouse mesangial cells. Clin Exp Immunol. 2009;156(3):542-551. https://doi.org/10.1111/j.1365-2249.2009.03924.x PMID:19438609 DOI: https://doi.org/10.1111/j.1365-2249.2009.03924.x

Bergmann C, Guay-Woodford LM, Harris PC, Horie S, Peters DJM, Torres VE. Polycystic kidney disease. Nat Rev Dis Primers. 2018;4(1):50. https://doi.org/10.1038/s41572-018-0047-y PMID:30523303 DOI: https://doi.org/10.1038/s41572-018-0047-y

Podrini C, Cassina L, Boletta A. Metabolic reprogramming and the role of mitochondria in polycystic kidney disease. Cell Signal. 2020;67:109495. https://doi.org/10.1016/j.cellsig.2019.109495 PMID:31816397 DOI: https://doi.org/10.1016/j.cellsig.2019.109495

Haumann S, Müller R-U, Liebau MC. Metabolic Changes in Polycystic Kidney Disease as a Potential Target for Systemic Treatment. Int J Mol Sci. 2020;21(17):6093. https://doi.org/10.3390/ijms21176093 PMID:32847032 DOI: https://doi.org/10.3390/ijms21176093

Takiar V, Nishio S, Seo-Mayer P, et al. Activating AMP-activated protein kinase (AMPK) slows renal cystogenesis. Proc Natl Acad Sci USA. 2011;108(6):2462-2467. https://doi.org/10.1073/pnas.1011498108 PMID:21262823 DOI: https://doi.org/10.1073/pnas.1011498108

Hawley SA, Ross FA, Chevtzoff C, et al. Use of cells expressing gamma subunit variants to identify diverse mechanisms of AMPK activation. Cell Metab. 2010;11(6):554-565. https://doi.org/10.1016/j.cmet.2010.04.001 PMID:20519126 DOI: https://doi.org/10.1016/j.cmet.2010.04.001

Miller RA, Chu Q, Xie J, Foretz M, Viollet B, Birnbaum MJ. Biguanides suppress hepatic glucagon signalling by decreasing production of cyclic AMP. Nature. 2013;494(7436):256-260. https://doi.org/10.1038/nature11808 PMID:23292513 DOI: https://doi.org/10.1038/nature11808

Chang M-Y, Ma T-L, Hung C-C, et al. Metformin Inhibits Cyst Formation in a Zebrafish Model of Polycystin-2 Deficiency. Sci Rep. 2017;7(1):7161. https://doi.org/10.1038/s41598-017-07300-x PMID:28769124 DOI: https://doi.org/10.1038/s41598-017-07300-x

Wang J, Chin D, Poon C, et al. Oral delivery of metformin by chitosan nanoparticles for polycystic kidney disease. J Control Release. 2021;329:1198-1209. https://doi.org/10.1016/j.jconrel.2020.10.047 PMID:33127449 DOI: https://doi.org/10.1016/j.jconrel.2020.10.047

Lian X, Wu X, Li Z, et al. The combination of metformin and 2-deoxyglucose significantly inhibits cyst formation in miniature pigs with polycystic kidney disease. Br J Pharmacol. 2019;176(5):711-724. https://doi.org/10.1111/bph.14558 PMID:30515768 DOI: https://doi.org/10.1111/bph.14558

Sato Y, Qiu J, Hirose T, et al. Metformin slows liver cyst formation and fibrosis in experimental model of polycystic liver disease. Am J Physiol Gastrointest Liver Physiol. 2021;320(4):G464-G473. https://doi.org/10.1152/ajpgi.00120.2020PMID:33439105 DOI: https://doi.org/10.1152/ajpgi.00120.2020

Metformin improves relevant disease parameters in an autosomal dominant. Núria M. Pastor-Soler, Hui Li, Jessica Pham, Daniel Rivera, Pei-Yin Ho, Valeria Mancino, Biagio Saitta, and Kenneth R. Hallows. s.l. Am J Physiol Renal Physiol. 2022;322:F27-F41. https://doi.org/10.1152/ajprenal.00298.2021 PMID: 34806449 DOI: https://doi.org/10.1152/ajprenal.00298.2021

Leonhard WN, Song X, Kanhai AA, et al. Salsalate, but not metformin or canagliflozin, slows kidney cyst growth in an adult-onset mouse model of polycystic kidney disease. EBioMedicine. 2019;47:436-445. https://doi.org/10.1016/j.ebiom.2019.08.041 PMID:31473186 DOI: https://doi.org/10.1016/j.ebiom.2019.08.041

Chang MY, Tsai TI, Chou LF, et al. Metformin induces lactate accumulation and accelerates renal cyst progression in Pkd1-deficient mice. Hum Mol Genet. 2021. https://doi.org/10.1093/hmg/ddab340 PMID:34957500 DOI: https://doi.org/10.1093/hmg/ddab340

Pisani A, Riccio E, Bruzzese D, Sabbatini M. Metformin in autosomal dominant polycystic kidney disease: experimental hypothesis or clinical fact? BMC Nephrol. 2018;19(1):282. https://doi.org/10.1186/s12882-018-1090-3 PMID:30348113 DOI: https://doi.org/10.1186/s12882-018-1090-3

Perrone RD, Abebe KZ, Watnick TJ, et al. Primary results of the randomized trial of metformin administration in polycystic kidney disease (TAME PKD). Kidney Int. 2021;100(3):684-696. https://doi.org/10.1016/j.kint.2021.06.013PMID:34186056 DOI: https://doi.org/10.1016/j.kint.2021.06.013

Brosnahan GM, Wang W, Gitomer B, Struemph T, George D, You Z, Nowak KL, Klawitter J, Chonchol MB. Metformin Therapy in Autosomal Dominant Polycystic Kidney Disease: A Feasibility Study. Am J Kidney Dis. 2021 Aug 12:S0272-6386(21)00790-3. https://doi.org/10.1053/j.ajkd.2021.06.026. PMID: 34391872. DOI: https://doi.org/10.1053/j.ajkd.2021.06.026

Spithoven EM, Kramer A, Meijer E, et al; ERA-EDTA Registry; EuroCYST Consortium; WGIKD; EuroCYST Consortium; WGIKD. Analysis of data from the ERA-EDTA Registry indicates that conventional treatments for chronic kidney disease do not reduce the need for renal replacement therapy in autosomal dominant polycystic kidney disease. Kidney Int. 2014;86(6):1244-1252. https://doi.org/10.1038/ki.2014.120 PMID:24827775 DOI: https://doi.org/10.1038/ki.2014.120

Woodhead JL, Pellegrini L, Shoda LKM, Howell BA. Comparison of the Hepatotoxic Potential of Two Treatments for Autosomal-Dominant Polycystic Kidney DiseaseUsing Quantitative Systems Toxicology Modeling. Pharm Res. 2020;37(2):24. https://doi.org/10.1007/s11095-019-2726-0 PMID:31909447 DOI: https://doi.org/10.1007/s11095-019-2726-0

Willey CJ, Blais JD, Hall AK, Krasa HB, Makin AJ, Czerwiec FS. Prevalence of autosomal dominant polycystic kidney disease in the European Union. Nephrol Dial Transplant. 2017;32(8):1356-1363. https://doi.org/10.1093/ndt/gfw240 PMID:27325254 DOI: https://doi.org/10.1093/ndt/gfw240

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Pubblicato

2022-04-30

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1.
Piscopo G. Metformina e rene policistico dell’adulto: tra ricerca e impiego clinico. G Clin Nefrol Dial [Internet]. 30 aprile 2022 [citato 20 maggio 2022];34(1):37-40. Available at: https://journals.aboutscience.eu/index.php/gcnd/article/view/2398

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Il rene policistico - In collaborazione con AIRP