The GranStone Trial

Summary

This study will investigate whether treatment with empagliflozin or losartan can reduce the risk of kidney stone formation in patients with paraffin disease, a condition caused by the injection of paraffin oil into muscle tissue for cosmetic muscle enlargement. Paraffin disease can lead to chronic inflammation, disturbances in calcium regulation, high blood calcium levels, kidney stones, and impaired kidney function. Previous studies from Herlev-Gentofte Hospital have shown that kidney stones occur in nearly half of affected patients, while approximately one-third develop reduced kidney function. Current treatment primarily consists of high-dose corticosteroids, which can reduce blood calcium levels but cause substantial adverse effects and may not adequately control the underlying disease process. Both empagliflozin and losartan are widely used medications with documented kidney-protective effects in other chronic kidney diseases. This randomized clinical trial will evaluate whether either treatment can prevent kidney stone formation and slow kidney-related complications in patients with paraffin disease. The purpose of this study is to determine whether treatment with empagliflozin or losartan can prevent kidney stone formation and improve kidney health in patients with paraffin disease.

Timeline

Start

2026-09

Primary completion

2029-03

Completion

2029-04

Publications

• Background World Medical Association. World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA. 2013 Nov 27;310(20):2191-4. doi: 10.1001/jama.2013.281053. No abstract available.
• Background The EMPA-KIDNEY Collaborative Group; Herrington WG, Staplin N, Wanner C, Green JB, Hauske SJ, Emberson JR, Preiss D, Judge P, Mayne KJ, Ng SYA, Sammons E, Zhu D, Hill M, Stevens W, Wallendszus K, Brenner S, Cheung AK, Liu ZH, Li J, Hooi LS, Liu W, Kadowaki T, Nangaku M, Levin A, Cherney D, Maggioni AP, Pontremoli R, Deo R, Goto S, Rossello X, Tuttle KR, Steubl D, Petrini M, Massey D, Eilbracht J, Brueckmann M, Landray MJ, Baigent C, Haynes R. Empagliflozin in Patients with Chronic Kidney Disease. N Engl J Med. 2023 Jan 12;388(2):117-127. doi: 10.1056/NEJMoa2204233. Epub 2022 Nov 4.
• Background Fares J, El Fadel O, Zhao J, Li M, Sun J, Roman J, Loizidis G, Summer R. Mortality and Health Outcomes Among Patients With Sarcoidosis Treated With Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers. Chest. 2025 Mar;167(3):772-780. doi: 10.1016/j.chest.2024.09.009. Epub 2024 Sep 21.
• Background Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, Remuzzi G, Snapinn SM, Zhang Z, Shahinfar S; RENAAL Study Investigators. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001 Sep 20;345(12):861-9. doi: 10.1056/NEJMoa011161.
• Background Crouser ED, Julian MW, Locke LW, Bicer S, Mitchell JR, Singha A, Kramer PJ, Rajaram MVS, Raman SV. The Renin-Angiotensin-Aldosterone System Regulates Sarcoidosis Granulomatous Inflammation. Am J Respir Crit Care Med. 2024 Aug 15;210(4):497-507. doi: 10.1164/rccm.202402-0265OC.
• Background Yahyavi SK, Theilade S, Hansen D, Berg JO, Andreassen CH, Lorenzen M, Jorgensen A, Juul A, Faber J, Eldrup E, Blomberg Jensen M. Treatment options for hypercalcemia after cosmetic oil injections: Lessons from human tissue cultures and a pilot intervention study. Bone. 2022 Jan;154:116244. doi: 10.1016/j.bone.2021.116244. Epub 2021 Oct 29.
• Background Yahyavi SK, Wall-Gremstrup G, Makki A, Juel J, Theilade S, Berg JO, Juul A, Momsen O, Eldrup E, Blomberg Jensen M. Debulking Surgery After Muscular Paraffin Oil Injections: Effects on Calcium Homeostasis and Patient Satisfaction. J Clin Endocrinol Metab. 2025 Feb 18;110(3):649-657. doi: 10.1210/clinem/dgae606.
• Background Willum-Hansen T, Staessen JA, Torp-Pedersen C, Rasmussen S, Thijs L, Ibsen H, Jeppesen J. Prognostic value of aortic pulse wave velocity as index of arterial stiffness in the general population. Circulation. 2006 Feb 7;113(5):664-70. doi: 10.1161/CIRCULATIONAHA.105.579342.
• Background Laurent S, Boutouyrie P, Asmar R, Gautier I, Laloux B, Guize L, Ducimetiere P, Benetos A. Aortic stiffness is an independent predictor of all-cause and cardiovascular mortality in hypertensive patients. Hypertension. 2001 May;37(5):1236-41. doi: 10.1161/01.hyp.37.5.1236.
• Background Schillaci G, Pucci G, Pirro M, Monacelli M, Scarponi AM, Manfredelli MR, Rondelli F, Avenia N, Mannarino E. Large-artery stiffness: a reversible marker of cardiovascular risk in primary hyperparathyroidism. Atherosclerosis. 2011 Sep;218(1):96-101. doi: 10.1016/j.atherosclerosis.2011.05.010. Epub 2011 May 18.
• Background Eldrup E, Theilade S, Lorenzen M, Andreassen CH, Poulsen KH, Nielsen JE, Hansen D, El Fassi D, Berg JO, Bagi P, Jorgensen A, Blomberg Jensen M. Hypercalcemia After Cosmetic Oil Injections: Unraveling Etiology, Pathogenesis, and Severity. J Bone Miner Res. 2021 Feb;36(2):322-333. doi: 10.1002/jbmr.4179. Epub 2020 Oct 13.
• Background Alexander RT, McArthur E, Jandoc R, Welk B, Hayward JS, Jain AK, Braam B, Flockerzi V, Garg AX, Quinn RR. Antihypertensive medications and the risk of kidney stones in older adults: a retrospective cohort study. Hypertens Res. 2017 Sep;40(9):837-842. doi: 10.1038/hr.2017.42. Epub 2017 Mar 23.
• Background Xie X, Liu Y, Perkovic V, Li X, Ninomiya T, Hou W, Zhao N, Liu L, Lv J, Zhang H, Wang H. Renin-Angiotensin System Inhibitors and Kidney and Cardiovascular Outcomes in Patients With CKD: A Bayesian Network Meta-analysis of Randomized Clinical Trials. Am J Kidney Dis. 2016 May;67(5):728-41. doi: 10.1053/j.ajkd.2015.10.011. Epub 2015 Nov 18.
• Background Anderegg MA, Schietzel S, Bargagli M, Bally L, Faller N, Moor MB, Cereghetti GM, Roumet M, Trelle S, Fuster DG. Empagliflozin in nondiabetic individuals with calcium and uric acid kidney stones: a randomized phase 2 trial. Nat Med. 2025 Jan;31(1):286-293. doi: 10.1038/s41591-024-03330-x. Epub 2025 Jan 2.
• Background Solomon SD, McMurray JJV, Claggett B, de Boer RA, DeMets D, Hernandez AF, Inzucchi SE, Kosiborod MN, Lam CSP, Martinez F, Shah SJ, Desai AS, Jhund PS, Belohlavek J, Chiang CE, Borleffs CJW, Comin-Colet J, Dobreanu D, Drozdz J, Fang JC, Alcocer-Gamba MA, Al Habeeb W, Han Y, Cabrera Honorio JW, Janssens SP, Katova T, Kitakaze M, Merkely B, O'Meara E, Saraiva JFK, Tereshchenko SN, Thierer J, Vaduganathan M, Vardeny O, Verma S, Pham VN, Wilderang U, Zaozerska N, Bachus E, Lindholm D, Petersson M, Langkilde AM; DELIVER Trial Committees and Investigators. Dapagliflozin in Heart Failure with Mildly Reduced or Preserved Ejection Fraction. N Engl J Med. 2022 Sep 22;387(12):1089-1098. doi: 10.1056/NEJMoa2206286. Epub 2022 Aug 27.
• Background Heerspink HJL, Stefansson BV, Correa-Rotter R, Chertow GM, Greene T, Hou FF, Mann JFE, McMurray JJV, Lindberg M, Rossing P, Sjostrom CD, Toto RD, Langkilde AM, Wheeler DC; DAPA-CKD Trial Committees and Investigators. Dapagliflozin in Patients with Chronic Kidney Disease. N Engl J Med. 2020 Oct 8;383(15):1436-1446. doi: 10.1056/NEJMoa2024816. Epub 2020 Sep 24.
• Background McMurray JJV, Solomon SD, Inzucchi SE, Kober L, Kosiborod MN, Martinez FA, Ponikowski P, Sabatine MS, Anand IS, Belohlavek J, Bohm M, Chiang CE, Chopra VK, de Boer RA, Desai AS, Diez M, Drozdz J, Dukat A, Ge J, Howlett JG, Katova T, Kitakaze M, Ljungman CEA, Merkely B, Nicolau JC, O'Meara E, Petrie MC, Vinh PN, Schou M, Tereshchenko S, Verma S, Held C, DeMets DL, Docherty KF, Jhund PS, Bengtsson O, Sjostrand M, Langkilde AM; DAPA-HF Trial Committees and Investigators. Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction. N Engl J Med. 2019 Nov 21;381(21):1995-2008. doi: 10.1056/NEJMoa1911303. Epub 2019 Sep 19.
• Background Lieben L, Carmeliet G, Masuyama R. Calcemic actions of vitamin D: effects on the intestine, kidney and bone. Best Pract Res Clin Endocrinol Metab. 2011 Aug;25(4):561-72. doi: 10.1016/j.beem.2011.05.008.
• Background Moraitis AG, Hewison M, Collins M, Anaya C, Holick MF. Hypercalcemia associated with mineral oil-induced sclerosing paraffinomas. Endocr Pract. 2013 Mar-Apr;19(2):e50-6. doi: 10.4158/EP12092.CR.
• Background Meyer MB, Pike JW. Mechanistic homeostasis of vitamin D metabolism in the kidney through reciprocal modulation of Cyp27b1 and Cyp24a1 expression. J Steroid Biochem Mol Biol. 2020 Feb;196:105500. doi: 10.1016/j.jsbmb.2019.105500. Epub 2019 Oct 16.
• Background Kundu R, Chain BM, Coussens AK, Khoo B, Noursadeghi M. Regulation of CYP27B1 and CYP24A1 hydroxylases limits cell-autonomous activation of vitamin D in dendritic cells. Eur J Immunol. 2014 Jun;44(6):1781-90. doi: 10.1002/eji.201344157. Epub 2014 Apr 10.
• Background Blomberg Jensen M. Vitamin D and male reproduction. Nat Rev Endocrinol. 2014 Mar;10(3):175-86. doi: 10.1038/nrendo.2013.262. Epub 2014 Jan 14.
• Background Tebben PJ, Singh RJ, Kumar R. Vitamin D-Mediated Hypercalcemia: Mechanisms, Diagnosis, and Treatment. Endocr Rev. 2016 Oct;37(5):521-547. doi: 10.1210/er.2016-1070. Epub 2016 Sep 2.
• Background Gyldenlove M, Rorvig S, Skov L, Hansen D. Severe hypercalcaemia, nephrocalcinosis, and multiple paraffinomas caused by paraffin oil injections in a young bodybuilder. Lancet. 2014 Jun 14;383(9934):2098. doi: 10.1016/S0140-6736(14)60806-0. No abstract available.
• Background Solling ASK, Tougaard BG, Harslof T, Langdahl B, Brockstedt HK, Byg KE, Ivarsen P, Ystrom IK, Mose FH, Isaksson GL, Hansen MSS, Nagarajah S, Ejersted C, Bendstrup E, Rejnmark L. Non-parathyroid hypercalcemia associated with paraffin oil injection in 12 younger male bodybuilders: a case series. Eur J Endocrinol. 2018 Jun;178(6):K29-K37. doi: 10.1530/EJE-18-0051. Epub 2018 Mar 29.
• Background Nerild HH, Theilade KS, Eldrup E. [Paraffin oil injecions due to bigorexia may cause hypercalcaemia]. Ugeskr Laeger. 2018 Nov 26;180(48):V04180256. Danish.
• Background Tachamo N, Donato A, Timilsina B, Nazir S, Lohani S, Dhital R, Basnet S. Hypercalcemia associated with cosmetic injections: a systematic review. Eur J Endocrinol. 2018 Apr;178(4):425-430. doi: 10.1530/EJE-17-0938. Epub 2018 Feb 16.
• Background Levy LL, Emer JJ. Complications of minimally invasive cosmetic procedures: prevention and management. J Cutan Aesthet Surg. 2012 Apr;5(2):121-32. doi: 10.4103/0974-2077.99451.

Drugs

Indications

No indication recorded.