A Crossover Pilot Study of the Effect of Amiloride on Proteinuria

Summary

This cross-over study is designed to test the hypothesis that amiloride will reduce urinary protein excretion and protect the kidney from rapid progression in proteinuric kidney disease.

Timeline

Start

2013-07

Primary completion

2021-10

Completion

2021-10

Publications

• Background Berhane AM, Weil EJ, Knowler WC, Nelson RG, Hanson RL. Albuminuria and estimated glomerular filtration rate as predictors of diabetic end-stage renal disease and death. Clin J Am Soc Nephrol. 2011 Oct;6(10):2444-51. doi: 10.2215/CJN.00580111. Epub 2011 Aug 18.
• Background Blasi F, Carmeliet P. uPAR: a versatile signalling orchestrator. Nat Rev Mol Cell Biol. 2002 Dec;3(12):932-43. doi: 10.1038/nrm977.
• Background Brown EA, Markandu ND, Roulston JE, Jones BE, Squires M, MacGregor GA. Is the renin-angiotensin-aldosterone system involved in the sodium retention in the nephrotic syndrome? Nephron. 1982;32(2):102-7. doi: 10.1159/000182827.
• Background Brown EA, Markandu ND, Sagnella GA, Jones BE, MacGregor GA. Lack of effect of captopril on the sodium retention of the nephrotic syndrome. Nephron. 1984;37(1):43-8. doi: 10.1159/000183206.
• Background Busch AE, Suessbrich H, Kunzelmann K, Hipper A, Greger R, Waldegger S, Mutschler E, Lindemann B, Lang F. Blockade of epithelial Na+ channels by triamterenes - underlying mechanisms and molecular basis. Pflugers Arch. 1996 Sep;432(5):760-6. doi: 10.1007/s004240050196.
• Background Geers AB, Koomans HA, Roos JC, Boer P, Dorhout Mees EJ. Functional relationships in the nephrotic syndrome. Kidney Int. 1984 Sep;26(3):324-30. doi: 10.1038/ki.1984.176.
• Background Randomised placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate and risk of terminal renal failure in proteinuric, non-diabetic nephropathy. The GISEN Group (Gruppo Italiano di Studi Epidemiologici in Nefrologia). Lancet. 1997 Jun 28;349(9069):1857-63.
• Background Hemmelgarn BR, Manns BJ, Lloyd A, James MT, Klarenbach S, Quinn RR, Wiebe N, Tonelli M; Alberta Kidney Disease Network. Relation between kidney function, proteinuria, and adverse outcomes. JAMA. 2010 Feb 3;303(5):423-9. doi: 10.1001/jama.2010.39.
• Background Iishi H, Tatsuta M, Baba M, Yano H, Uehara H, Nakaizumi A. Suppression by amiloride of bombesin-enhanced peritoneal metastasis of intestinal adenocarcinomas induced by azoxymethane. Int J Cancer. 1995 Nov 27;63(5):716-9. doi: 10.1002/ijc.2910630518.
• Background Kellen JA, Mirakian A, Kolin A. Antimetastatic effect of amiloride in an animal tumour model. Anticancer Res. 1988 Nov-Dec;8(6):1373-6.
• Background Laurens WE, Vanrenterghem YF, Steels PS, Van Damme BJ. A new single nephron model of focal and segmental glomerulosclerosis in the Munich-Wistar rat. Kidney Int. 1994 Jan;45(1):143-9. doi: 10.1038/ki.1994.17.
• Background Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. N Engl J Med. 1993 Nov 11;329(20):1456-62. doi: 10.1056/NEJM199311113292004.
• Background Madsen CD, Ferraris GM, Andolfo A, Cunningham O, Sidenius N. uPAR-induced cell adhesion and migration: vitronectin provides the key. J Cell Biol. 2007 Jun 4;177(5):927-39. doi: 10.1083/jcb.200612058.
• Background Mathieson PW. Proteinuria and immunity--an overstated relationship? N Engl J Med. 2008 Dec 4;359(23):2492-4. doi: 10.1056/NEJMcibr0806881. No abstract available.
• Background Meltzer JI, Keim HJ, Laragh JH, Sealey JE, Jan KM, Chien S. Nephrotic syndrome: vasoconstriction and hypervolemic types indicated by renin-sodium profiling. Ann Intern Med. 1979 Nov;91(5):688-96. doi: 10.7326/0003-4819-91-5-688.
• Background Reiser J, Oh J, Shirato I, Asanuma K, Hug A, Mundel TM, Honey K, Ishidoh K, Kominami E, Kreidberg JA, Tomino Y, Mundel P. Podocyte migration during nephrotic syndrome requires a coordinated interplay between cathepsin L and alpha3 integrin. J Biol Chem. 2004 Aug 13;279(33):34827-32. doi: 10.1074/jbc.M401973200. Epub 2004 Jun 14.
• Background Rennke HG. How does glomerular epithelial cell injury contribute to progressive glomerular damage? Kidney Int Suppl. 1994 Feb;45:S58-63.
• Background Sepehrdad R, Chander PN, Oruene A, Rosenfeld L, Levine S, Stier CT Jr. Amiloride reduces stroke and renalinjury in stroke-prone hypertensive rats. Am J Hypertens. 2003 Apr;16(4):312-8. doi: 10.1016/s0895-7061(03)00006-2.
• Background Thuno M, Macho B, Eugen-Olsen J. suPAR: the molecular crystal ball. Dis Markers. 2009;27(3):157-72. doi: 10.3233/DMA-2009-0657.
• Background Trivedi S, Zeier M, Reiser J. Role of podocytes in lupus nephritis. Nephrol Dial Transplant. 2009 Dec;24(12):3607-12. doi: 10.1093/ndt/gfp427. Epub 2009 Sep 3. No abstract available.
• Background Usberti M, Federico S, Meccariello S, Cianciaruso B, Balletta M, Pecoraro C, Sacca L, Ungaro B, Pisanti N, Andreucci VE. Role of plasma vasopressin in the impairment of water excretion in nephrotic syndrome. Kidney Int. 1984 Feb;25(2):422-9. doi: 10.1038/ki.1984.34.
• Background Vande Walle J, Donckerwolcke R, Boer P, van Isselt HW, Koomans HA, Joles JA. Blood volume, colloid osmotic pressure and F-cell ratio in children with the nephrotic syndrome. Kidney Int. 1996 May;49(5):1471-7. doi: 10.1038/ki.1996.207. No abstract available.
• Background Vande Walle JG, Donckerwolcke RA, Koomans HA. Pathophysiology of edema formation in children with nephrotic syndrome not due to minimal change disease. J Am Soc Nephrol. 1999 Feb;10(2):323-31. doi: 10.1681/ASN.V102323.
• Background Wang Y, Jones CJ, Dang J, Liang X, Olsen JE, Doe WF. Human urokinase receptor expression is inhibited by amiloride and induced by tumor necrosis factor and phorbol ester in colon cancer cells. FEBS Lett. 1994 Oct 17;353(2):138-42. doi: 10.1016/0014-5793(94)01032-3.
• Background Wei C, El Hindi S, Li J, Fornoni A, Goes N, Sageshima J, Maiguel D, Karumanchi SA, Yap HK, Saleem M, Zhang Q, Nikolic B, Chaudhuri A, Daftarian P, Salido E, Torres A, Salifu M, Sarwal MM, Schaefer F, Morath C, Schwenger V, Zeier M, Gupta V, Roth D, Rastaldi MP, Burke G, Ruiz P, Reiser J. Circulating urokinase receptor as a cause of focal segmental glomerulosclerosis. Nat Med. 2011 Jul 31;17(8):952-60. doi: 10.1038/nm.2411.
• Background Wei C, Moller CC, Altintas MM, Li J, Schwarz K, Zacchigna S, Xie L, Henger A, Schmid H, Rastaldi MP, Cowan P, Kretzler M, Parrilla R, Bendayan M, Gupta V, Nikolic B, Kalluri R, Carmeliet P, Mundel P, Reiser J. Modification of kidney barrier function by the urokinase receptor. Nat Med. 2008 Jan;14(1):55-63. doi: 10.1038/nm1696. Epub 2007 Dec 16.
• Background Wei C, Trachtman H, Li J, Dong C, Friedman AL, Gassman JJ, McMahan JL, Radeva M, Heil KM, Trautmann A, Anarat A, Emre S, Ghiggeri GM, Ozaltin F, Haffner D, Gipson DS, Kaskel F, Fischer DC, Schaefer F, Reiser J; PodoNet and FSGS CT Study Consortia. Circulating suPAR in two cohorts of primary FSGS. J Am Soc Nephrol. 2012 Dec;23(12):2051-9. doi: 10.1681/ASN.2012030302. Epub 2012 Nov 8.
• Background Wei Y, Waltz DA, Rao N, Drummond RJ, Rosenberg S, Chapman HA. Identification of the urokinase receptor as an adhesion receptor for vitronectin. J Biol Chem. 1994 Dec 23;269(51):32380-8.
• Background Wu S, Murrell GA, Wang Y. Interferon-alpha (Intron A) upregulates urokinase-type plasminogen activator receptor gene expression. Cancer Immunol Immunother. 2002 Jul;51(5):248-54. doi: 10.1007/s00262-002-0275-5. Epub 2002 Apr 9.
• Background Zhang B, Xie S, Shi W, Yang Y. Amiloride off-target effect inhibits podocyte urokinase receptor expression and reduces proteinuria. Nephrol Dial Transplant. 2012 May;27(5):1746-55. doi: 10.1093/ndt/gfr612. Epub 2011 Nov 9.
• Shen W, Alshehri M, Desale S, Wilcox C. The Effect of Amiloride on Proteinuria in Patients with Proteinuric Kidney Disease. Am J Nephrol. 2021;52(5):368-377. doi: 10.1159/000515809. Epub 2021 May 6.

Drugs

Indications