Octreotide Lar in Patients with Autosomal Dominant Polycystic Kidney Disease: From Bench to A Novel Perspective of Therapy The History of Octreotide LAR in ADPKD

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Piero Ruggenenti Annalisa Perna Anna Caroli Norberto Perico Matias Trillini Antonio Pisani Letizia Spinelli Giuseppe Remuzzi


Polycystins 1 or 2 congenital defects result in impaired Ca2+ inflow through the tubular cell membrane with reduced intracellular Ca2+ concentration and secondary adenylcyclase over-activation with increased intracellular cAMP. This activates chloride-driven fluid secretion and tubular cell proliferation and de-differentiation with cyst formation and growth. Thus, medications, such as the somatostatin analogue Octreotide LAR or the vasopressin antagonist Tolvaptan, that reduce intracellular cAMP, have been tested to inhibit cAMP-mediated chloride secretion and cell proliferation in experimental and human polycystic kidney disease. Seminal studies conducted in the early ‘80s by Franklin Epstein showed that in the shark rectal gland chloride secretion is markedly inhibited by somatostatin in a way suggesting inhibition of adenylcyclase. Evidence that specific receptors for somatostatin, in particular the sst2 subtype, are present in tubular cell membranes suggested that Octreotide LAR binding to its specific renal receptors could exert similar effects in ADPKD cells. In a pilot, cross-over safety study we found that 6-month Octreotide LAR therapy was safe and well tolerated in 12 patients with ADPKD and significantly decreased total kidney volume growth as compared to placebo. Then, the ALADIN and ALADIN II academic, prospective, randomized, placebo-controlled clinical trials found that 3-year Octreotide LAR treatment significantly slowed total kidney and cyst volume growth. In ALADIN treatment slowed chronic decline of directly measured GFR in 79 patients with estimated GFR ≥ 40 ml/min/1.73 m2. In ALADIN II treatment slowed progression to doubling of serum creatinine or ESKD in 100 patients with stage 3b-4 CKD. Treatment was equally safe and well tolerated in both studies. Sub-studies also showed that 3-year Octreotide LAR therapy reduced total liver volume in 27 ADPKD patients with associated polycystic livers and improved left ventricular twisting and untwisting function in 34 ADPKD patients assessed by speckled-tracked echocardiography. Future trials should confirm the long-term benefits of Octreotide LAR in larger populations of ADPKD patients. Moreover, recent studies found that somatostatin analogues and Tolvaptan have additional beneficial effects in experimental polycystic kidney disease. Thus, clinical trials should also explore whether Octreotide LAR and Tolvaptan in combined therapy may have an additional beneficial effect even in human disease.

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RUGGENENTI, Piero et al. Octreotide Lar in Patients with Autosomal Dominant Polycystic Kidney Disease: From Bench to A Novel Perspective of Therapy. Medical Research Archives, [S.l.], v. 10, n. 12, dec. 2022. ISSN 2375-1924. Available at: <https://esmed.org/MRA/mra/article/view/3232>. Date accessed: 29 jan. 2023. doi: https://doi.org/10.18103/mra.v10i12.3232.
Research Articles


1. Gabow PA. Autosomal dominant polycystic kidney disease. N Engl J Med. 1993;329(5):332-342. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=8321262
2. Klahr S, Breyer JA, Beck GJ, et al. Dietary protein restriction, blood pressure control, and the progression of polycystic kidney disease. Modification of Diet in Renal Disease Study Group. J Am Soc Nephrol JASN. 1995;5(12):2037-2047. doi:10.1681/ASN.V5122037
3. Ecder T, Chapman AB, Brosnahan GM, Edelstein CL, Johnson AM, Schrier RW. Effect of antihypertensive therapy on renal function and urinary albumin excretion in hypertensive patients with autosomal dominant polycystic kidney disease. Am J Kidney Dis Off J Natl Kidney Found. 2000;35(3):427-432. doi:10.1016/s0272-6386(00)70195-8
4. Torres VE. Hypertension, proteinuria, and progression of autosomal dominant polycystic kidney disease: where do we go from here? Am J Kidney Dis. 2000;35(3):547-550. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10692286
5. Schrier RW, Abebe KZ, Perrone RD, et al. Blood pressure in early autosomal dominant polycystic kidney disease. N Engl J Med. 2014;371(24):2255-2266. doi:10.1056/NEJMoa1402685
6. Torres VE, Abebe KZ, Chapman AB, et al. Angiotensin blockade in late autosomal dominant polycystic kidney disease. N Engl J Med. 2014;371(24):2267-2276. doi:10.1056/NEJMoa1402686
7. King BF, Reed JE, Bergstralh EJ, Sheedy PF 2nd, Torres VE. Quantification and longitudinal trends of kidney, renal cyst, and renal parenchyma volumes in autosomal dominant polycystic kidney disease. J Am Soc Nephrol. 2000;11(8):1505-1511. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10906164
8. Abbate M, Zoja C, Morigi M, et al. Trasforming growth factor-b1 is up-regulated by podocytes in response to excess intraglomerular passage of proteins. Am J Pathol. 2002;161:2179-2193.
9. Parfrey PS, Bear JC, Morgan J, et al. The diagnosis and prognosis of autosomal dominant polycystic kidney disease. N Engl J Med. 1990;323(16):1085-1090. doi:10.1056/NEJM199010183231601
10. Heerspink HJL, Stefánsson BV, Correa-Rotter R, et al. Dapagliflozin in Patients with Chronic Kidney Disease. N Engl J Med. 2020;383(15):1436-1446. doi:10.1056/NEJMoa2024816
11. Rodriguez D, Kapoor S, Edenhofer I, et al. Inhibition of Sodium-Glucose Cotransporter 2 with Dapagliflozin in Han: SPRD Rats with Polycystic Kidney Disease. Kidney Blood Press Res. 2015;40(6):638-647. doi:10.1159/000368540
12. Kapoor S, Rodriguez D, Riwanto M, et al. Effect of Sodium-Glucose Cotransport Inhibition on Polycystic Kidney Disease Progression in PCK Rats. PloS One. 2015;10(4):e0125603. doi:10.1371/journal.pone.0125603
13. Forrest JN. A tribute to Franklin H. Epstein. J Clin Invest. 2009;119(2):238-239. doi:10.1172/JCI38469
14. Silva P, Stoff JS, Leone DR, Epstein FH. Mode of action of somatostatin to inhibit secretion by shark rectal gland. Am J Physiol. 1985;249(3 Pt 2):R329-34. http://www.ncbi.nlm.nih.gov/pubmed/2863985
15. Epstein FH. A Laboratory by the Sea: The Mount Desert Island Biological Laboratory 1898-1998. The River Press; 1998.
16. Ruggenenti P, Remuzzi A, Ondei P, et al. Safety and efficacy of long-acting somatostatin treatment in autosomal-dominant polycystic kidney disease. Kidney Int. 2005;68(1):206-216. doi:10.1111/j.1523-1755.2005.00395.x
17. Sullivan LP, Wallace DP, Grantham JJ. Epithelial transport in polycystic kidney disease. Physiol Rev. 1998;78(4):1165-1191. doi:10.1152/physrev.1998.78.4.1165
18. Sullivan LP, Wallace DP, Grantham JJ. Chloride and fluid secretion in polycystic kidney disease. J Am Soc Nephrol JASN. 1998;9(5):903-916. doi:10.1681/ASN.V95903
19. Wallace DP, Grantham JJ, Sullivan LP. Chloride and fluid secretion by cultured human polycystic kidney cells. Kidney Int. 1996;50(4):1327-1336. doi:10.1038/ki.1996.445
20. Beyenbach KW, Frömter E. Electrophysiological evidence for Cl secretion in shark renal proximal tubules. Am J Physiol. 1985;248(2 Pt 2):F282-295. doi:10.1152/ajprenal.1985.248.2.F282
21. Beyenbach KW, Liu PL. Mechanism of fluid secretion common to aglomerular and glomerular kidneys. Kidney Int. 1996;49(6):1543-1548. doi:10.1038/ki.1996.221
22. Epstein FH, Stoff JS, Silva P. Mechanism and control of hyperosmotic NaCl-rich secretion by the rectal gland of Squalus acanthias. J Exp Biol. 1983;106:25-41. doi:10.1242/jeb.106.1.25
23. Torres VE, Harris PC, Pirson Y. Autosomal dominant polycystic kidney disease. Lancet. 2007;369(9569):1287-1301. doi:10.1016/S0140-6736(07)60601-1
24. Hopp K, Hommerding CJ, Wang X, Ye H, Harris PC, Torres VE. Tolvaptan plus pasireotide shows enhanced efficacy in a PKD1 model. J Am Soc Nephrol JASN. 2015;26(1):39-47. doi:10.1681/ASN.2013121312
25. Gattone VH, 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. doi:10.1038/nm935
26. Reubi JC, Horisberger U, Studer UE, Waser B, Laissue JA. Human kidney as target for somatostatin: high affinity receptors in tubules and vasa recta. J Clin Endocrinol Metab. 1993;77(5):1323-1328. doi:10.1210/jcem.77.5.7915721
27. Reichlin S. Somatostatin. N Engl J Med. 1983;309(24):1495-1501. doi:10.1056/NEJM198312153092406
28. Lamberts SW, van der Lely AJ, de Herder WW, Hofland LJ. Octreotide. N Engl J Med. 1996;334(4):246-254. doi:10.1056/NEJM199601253340408
29. Trendle MC, Moertel CG, Kvols LK. Incidence and morbidity of cholelithiasis in patients receiving chronic octreotide for metastatic carcinoid and malignant islet cell tumors. Cancer. 1997;79(4):830-834. doi:10.1002/(sici)1097-0142(19970215)79:4<830::aid-cncr20>3.0.co;2-#
30. Gaspari F, Perico N, Ruggenenti P, et al. Plasma clearance of nonradioactive iohexol as a measure of glomerular filtration rate. J Am Soc Nephrol. 1995;6(2):257-263. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=7579093
31. Redfern JS, Fortuner WJ. Octreotide-associated biliary tract dysfunction and gallstone formation: pathophysiology and management. Am J Gastroenterol. 1995;90(7):1042-1052.
32. Hogan MC, Chamberlin JA, Vaughan LE, et al. Pansomatostatin Agonist Pasireotide Long-Acting Release for Patients with Autosomal Dominant Polycystic Kidney or Liver Disease with Severe Liver Involvement: A Randomized Clinical Trial. Clin J Am Soc Nephrol CJASN. 2020;15(9):1267-1278. doi:10.2215/CJN.13661119
33. Bolanowski M, Kałużny M, Witek P, Jawiarczyk-Przybyłowska A. Pasireotide-a novel somatostatin receptor ligand after 20 years of use. Rev Endocr Metab Disord. 2022;23(3):601-620. doi:10.1007/s11154-022-09710-3
34. Cortinovis M, Perico N, Ruggenenti P, Remuzzi A, Remuzzi G. Glomerular hyperfiltration. Nat Rev Nephrol. 2022;18(7):435-451. doi:10.1038/s41581-022-00559-y
35. Caroli A, Perico N, Perna A, et al. Effect of longacting somatostatin analogue on kidney and cyst growth in autosomal dominant polycystic kidney disease (ALADIN): a randomised, placebo-controlled, multicentre trial. Lancet. 2013;382(9903):1485-1495. doi:10.1016/S0140-6736(13)61407-5
36. Torres VE, Chapman AB, Devuyst O, et al. Tolvaptan in patients with autosomal dominant polycystic kidney disease. N Engl J Med. 2012;367(25):2407-2418. doi:10.1056/NEJMoa1205511
37. Irazabal MV, Torres VE, Hogan MC, et al. Short-term effects of tolvaptan on renal function and volume in patients with autosomal dominant polycystic kidney disease. Kidney Int. 2011;80(3):295-301. doi:10.1038/ki.2011.119
38. Brouhard BH, LaGrone LF, Richards GE, Travis LB. Somatostatin limits rise in glomerular filtration rate after a protein meal. J Pediatr. 1987;110(5):729-734. http://www.ncbi.nlm.nih.gov/pubmed/2883274
39. Vora J, Owens DR, Luzio S, Atiea J, Ryder R, Hayes TM. Renal response to intravenous somatostatin in insulin-dependent diabetic patients and normal subjects. J Clin Endocrinol Metab. 1987;64(5):975-979. doi:10.1210/jcem-64-5-975
40. Gines A, Salmeron JM, Gines P, et al. Effects of somatostatin on renal function in cirrhosis. Gastroenterology. 1992;103(6):1868-1874. http://www.ncbi.nlm.nih.gov/pubmed/1360435
41. Colao A, Petersenn S, Newell-Price J, et al. A 12-month phase 3 study of pasireotide in Cushing’s disease. N Engl J Med. 2012;366(10):914-924. doi:10.1056/NEJMoa1105743
42. Helal I, Reed B, McFann K, et al. Glomerular hyperfiltration and renal progression in children with autosomal dominant polycystic kidney disease. Clin J Am Soc Nephrol. 2011;6(10):2439-2443. doi:10.2215/CJN.01010211
43. Grantham JJ. Clinical practice. Autosomal dominant polycystic kidney disease. N Engl J Med. 2008;359(14):1477-1485. doi:10.1056/NEJMcp0804458
44. Bigg-Wither GW, Ho KK, Grunstein RR, Sullivan CE, Doust BD. Effects of long term octreotide on gall stone formation and gall bladder function. BMJ. 1992;304(6842):1611-1612. doi:10.1136/bmj.304.6842.1611
45. Ruggenenti P, Cravedi P, Remuzzi G. Mechanisms and treatment of CKD. J Am Soc Nephrol. 2012;23(12):1917-1928. doi:10.1681/ASN.2012040390
46. Jafar TH, Stark PC, Schmid CH, et al. Proteinuria as a modifiable risk factor for the progression of non-diabetic renal disease. Kidney Int. 2001;60(3):1131-1140. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11532109
47. Hogan MC, Masyuk TV, Page LJ, et al. Randomized clinical trial of long-acting somatostatin for autosomal dominant polycystic kidney and liver disease. J Am Soc Nephrol. 2010;21(6):1052-1061. doi:10.1681/ASN.2009121291
48. McKeage K, Cheer S, Wagstaff AJ. Octreotide long-acting release (LAR): a review of its use in the management of acromegaly. Drugs. 2003;63(22):2473-2499. doi:10.2165/00003495-200363220-00014
49. Broder MS, Beenhouwer D, Strosberg JR, Neary MP, Cherepanov D. Gastrointestinal neuroendocrine tumors treated with high dose octreotide LAR: a systematic literature review. World J Gastroenterol. 2015;21(6):1945-1955. doi:10.3748/wjg.v21.i6.1945
50. Solazzo A, Testa F, Giovanella S, et al. The prevalence of autosomal dominant polycystic kidney disease (ADPKD): A meta-analysis of European literature and prevalence evaluation in the Italian province of Modena suggest that ADPKD is a rare and underdiagnosed condition. PLoS One. 2018;13(1):e0190430. doi:10.1371/journal.pone.0190430
51. Meijer E, Visser FW, van Aerts RMM, et al. Effect of Lanreotide on Kidney Function in Patients With Autosomal Dominant Polycystic Kidney Disease: The DIPAK 1 Randomized Clinical Trial. JAMA. 2018;320(19):2010-2019. doi:10.1001/jama.2018.15870
52. Porrini E, Ruggenenti P, Luis-Lima S, et al. Estimated GFR: time for a critical appraisal. Nat Rev Nephrol. 2019;15(3):177-190. doi:10.1038/s41581-018-0080-9
53. Rodríguez RM, Luis-Lima S, Fernandez JM, et al. Estimated GFR in autosomal dominant polycystic kidney disease: errors of an unpredictable method. J Nephrol. Published online March 31, 2022. doi:10.1007/s40620-022-01286-0
54. Ruggenenti P, Gaspari F, Cannata A, et al. Measuring and estimating GFR and treatment effect in ADPKD patients: results and implications of a longitudinal cohort study. PLoS One. 2012;7(2):e32533. doi:10.1371/journal.pone.0032533
55. Messchendorp AL, Casteleijn NF, Meijer E, Gansevoort RT. Somatostatin in renal physiology and autosomal dominant polycystic kidney disease. Nephrol Dial Transplant Off Publ Eur Dial Transpl Assoc - Eur Ren Assoc. 2020;35(8):1306-1316. doi:10.1093/ndt/gfz054
56. Lantinga MA, D’Agnolo HMA, Casteleijn NF, et al. Hepatic Cyst Infection During Use of the Somatostatin Analog Lanreotide in Autosomal Dominant Polycystic Kidney Disease: An Interim Analysis of the Randomized Open-Label Multicenter DIPAK-1 Study. Drug Saf. 2017;40(2):153-167. doi:10.1007/s40264-016-0486-x
57. Rosen AN, Balazh JR, Franck AJ. Severe hyperglycemia following transition from octreotide to lanreotide in a patient with enterocutaneous fistula receiving parenteral nutrition. Nutr Clin Pract Off Publ Am Soc Parenter Enter Nutr. 2022;37(3):727-731. doi:10.1002/ncp.10757
58. Van Keimpema L, De Koning DB, Van Hoek B, et al. Patients with isolated polycystic liver disease referred to liver centres: clinical characterization of 137 cases. Liver Int. 2011;31(1):92-98. doi:10.1111/j.1478-3231.2010.02247.x
59. Reynolds DM, Falk CT, Li A, et al. Identification of a locus for autosomal dominant polycystic liver disease, on chromosome 19p13.2-13.1. Am J Hum Genet. 2000;67(6):1598-1604. doi:10.1086/316904
60. Bae KT, Zhu F, Chapman AB, et al. Magnetic resonance imaging evaluation of hepatic cysts in early autosomal-dominant polycystic kidney disease: the Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease cohort. Clin J Am Soc Nephrol. 2006;1(1):64-69. doi:10.2215/CJN.00080605
61. Wijnands TF, Neijenhuis MK, Kievit W, et al. Evaluating health-related quality of life in patients with polycystic liver disease and determining the impact of symptoms and liver volume. Liver Int. 2014;34(10):1578-1583. doi:10.1111/liv.12430
62. Torres VE, Rastogi S, King BF, Stanson AW, Gross JB Jr, Nogorney DM. Hepatic venous outflow obstruction in autosomal dominant polycystic kidney disease. J Am Soc Nephrol. 1994;5(5):1186-1192. http://www.ncbi.nlm.nih.gov/pubmed/7873728
63. Belibi FA, Reif G, Wallace DP, et al. Cyclic AMP promotes growth and secretion in human polycystic kidney epithelial cells. Kidney Int. 2004;66(3):964-973. doi:10.1111/j.1523-1755.2004.00843.x
64. Caroli A, Antiga L, Cafaro M, et al. Reducing polycystic liver volume in ADPKD: effects of somatostatin analogue octreotide. Clin J Am Soc Nephrol. 2010;5(5):783-789. doi:10.2215/CJN.05380709
65. Masyuk TV, Masyuk AI, Torres VE, Harris PC, Larusso NF. Octreotide inhibits hepatic cystogenesis in a rodent model of polycystic liver disease by reducing cholangiocyte adenosine 3’,5’-cyclic monophosphate. Gastroenterology. 2007;132(3):1104-1116. doi:10.1053/j.gastro.2006.12.039
66. Volk T, Schwoerer AP, Thiessen S, Schultz JH, Ehmke H. A polycystin-2-like large conductance cation channel in rat left ventricular myocytes. Cardiovasc Res. 2003;58(1):76-88. doi:10.1016/s0008-6363(02)00858-1
67. Gevers TJ, Inthout J, Caroli A, et al. Young women with polycystic liver disease respond best to somatostatin analogues: a pooled analysis of individual patient data. Gastroenterology. 2013;145(2):357-65 e1-2. doi:10.1053/j.gastro.2013.04.055
68. Chrispijn M, Nevens F, Gevers TJ, et al. The long-term outcome of patients with polycystic liver disease treated with lanreotide. Aliment Pharmacol Ther. 2012;35(2):266-274. doi:10.1111/j.1365-2036.2011.04923.x
69. Acromegaly Therapy Consensus Development Panel. Consensus statement: benefits versus risks of medical therapy for acromegaly. Am J Med. 1994;97(5):468-473. doi:10.1016/0002-9343(94)90327-1
70. Giustina A, Mazziotti G, Torri V, Spinello M, Floriani I, Melmed S. Meta-analysis on the effects of octreotide on tumor mass in acromegaly. PLoS One. 2012;7(5):e36411. doi:10.1371/journal.pone.0036411
71. Wilson PD. Polycystin: new aspects of structure, function, and regulation. J Am Soc Nephrol JASN. 2001;12(4):834-845. doi:10.1681/ASN.V124834
72. Pedrozo Z, Criollo A, Battiprolu PK, et al. Polycystin-1 Is a Cardiomyocyte Mechanosensor That Governs L-Type Ca2+ Channel Protein Stability. Circulation. 2015;131(24):2131-2142. doi:10.1161/CIRCULATIONAHA.114.013537
73. Anyatonwu GI, Estrada M, Tian X, Somlo S, Ehrlich BE. Regulation of ryanodine receptor-dependent calcium signaling by polycystin-2. Proc Natl Acad Sci U S A. 2007;104(15):6454-6459. doi:10.1073/pnas.0610324104
74. Wallace DP. Cyclic AMP-mediated cyst expansion. Biochim Biophys Acta. 2011;1812(10):1291-1300. doi:10.1016/j.bbadis.2010.11.005
75. Paavola J, Schliffke S, Rossetti S, et al. Polycystin-2 mutations lead to impaired calcium cycling in the heart and predispose to dilated cardiomyopathy. J Mol Cell Cardiol. 2013;58:199-208. doi:10.1016/j.yjmcc.2013.01.015
76. Smith WH, Nair RU, Adamson D, Kearney MT, Ball SG, Balmforth AJ. Somatostatin receptor subtype expression in the human heart: differential expression by myocytes and fibroblasts. J Endocrinol. 2005;187(3):379-386. doi:10.1677/joe.1.06082
77. Reisner SA, Lysyansky P, Agmon Y, Mutlak D, Lessick J, Friedman Z. Global longitudinal strain: a novel index of left ventricular systolic function. J Am Soc Echocardiogr. 2004;17(6):630-633. doi:10.1016/j.echo.2004.02.011
78. Mor-Avi V, Lang RM, Badano LP, et al. Current and evolving echocardiographic techniques for the quantitative evaluation of cardiac mechanics: ASE/EAE consensus statement on methodology and indications endorsed by the Japanese Society of Echocardiography. Eur J Echocardiogr J Work Group Echocardiogr Eur Soc Cardiol. 2011;12(3):167-205. doi:10.1093/ejechocard/jer021
79. Nagueh SF, Smiseth OA, Appleton CP, et al. Recommendations for the Evaluation of Left Ventricular Diastolic Function by Echocardiography: An Update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. Eur Heart J Cardiovasc Imaging. 2016;17(12):1321-1360. doi:10.1093/ehjci/jew082
80. Notomi Y, Lysyansky P, Setser RM, et al. Measurement of ventricular torsion by two-dimensional ultrasound speckle tracking imaging. J Am Coll Cardiol. 2005;45(12):2034-2041. doi:10.1016/j.jacc.2005.02.082
81. Amundsen BH, Helle-Valle T, Edvardsen T, et al. Noninvasive myocardial strain measurement by speckle tracking echocardiography: validation against sonomicrometry and tagged magnetic resonance imaging. J Am Coll Cardiol. 2006;47(4):789-793. doi:10.1016/j.jacc.2005.10.040
82. Goffinet C, Chenot F, Robert A, et al. Assessment of subendocardial vs. subepicardial left ventricular rotation and twist using two-dimensional speckle tracking echocardiography: comparison with tagged cardiac magnetic resonance. Eur Heart J. 2009;30(5):608-617. doi:10.1093/eurheartj/ehn511
83. Wang J, Khoury DS, Yue Y, Torre-Amione G, Nagueh SF. Left ventricular untwisting rate by speckle tracking echocardiography. Circulation. 2007;116(22):2580-2586. doi:10.1161/CIRCULATIONAHA.107.706770
84. Hirai S, Hasegawa J, Mashiba H. Positive inotropic effect of somatostatin in guinea-pig ventricular muscles. J Mol Cell Cardiol. 1989;21(6):607-616. http://www.ncbi.nlm.nih.gov/pubmed/2570876
85. Ecder T, Schrier RW. Cardiovascular abnormalities in autosomal-dominant polycystic kidney disease. Nat Rev Nephrol. 2009;5(4):221-228. doi:10.1038/nrneph.2009.13
86. Pisani A, Sabbatini M, Imbriaco M, et al. Long-term Effects of Octreotide on Liver Volume in Patients With Polycystic Kidney and Liver Disease. Clin Gastroenterol Hepatol. 2016;14(7):1022-1030 e4. doi:10.1016/j.cgh.2015.12.049
87. Capuano I, Buonanno P, Riccio E, Rizzo M, Pisani A. Tolvaptan vs. somatostatin in the treatment of ADPKD: A review of the literature. Clin Nephrol. 2022;97(3):131-140. doi:10.5414/CN110510
88. Torres VE, Harris PC. Strategies targeting cAMP signaling in the treatment of polycystic kidney disease. J Am Soc Nephrol. 2014;25(1):18-32. doi:10.1681/ASN.2013040398
89. Boertien WE, Meijer E, de Jong PE, et al. Short-term renal hemodynamic effects of tolvaptan in subjects with autosomal dominant polycystic kidney disease at various stages of chronic kidney disease. Kidney Int. 2013;84(6):1278-1286. doi:10.1038/ki.2013.285
90. Perico N, Ruggenenti P, Perna A, et al. 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. doi:10.1371/journal.pmed.1002777
91. Grantham JJ, Torres VE, Chapman AB, et al. Volume progression in polycystic kidney disease. N Engl J Med. 2006;354(20):2122-2130. doi:10.1056/NEJMoa054341
92. Fleseriu M, Dreval A, Bondar I, et al. Maintenance of response to oral octreotide compared with injectable somatostatin receptor ligands in patients with acromegaly: a phase 3, multicentre, randomised controlled trial. Lancet Diabetes Endocrinol. 2022;10(2):102-111. doi:10.1016/S2213-8587(21)00296-5