Clinical proof-of-concept trial to assess the therapeutic effect of sirolimus in patients with autosomal dominant polycystic kidney disease: SUISSE ADPKD study

Andreas L Serra, Andreas D Kistler, Diane Poster, Marian Struker, Rudolf P Wüthrich, Dominik Weishaupt, Frank Tschirch, Andreas L Serra, Andreas D Kistler, Diane Poster, Marian Struker, Rudolf P Wüthrich, Dominik Weishaupt, Frank Tschirch

Abstract

Background: Currently there is no effective treatment available to retard cyst growth and to prevent the progression to end-stage renal failure in patients with autosomal dominant polycystic kidney disease (ADPKD). Evidence has recently been obtained from animal experiments that activation of the mammalian target of rapamycin (mTOR) signaling pathway plays a crucial role in cyst growth and renal volume expansion, and that the inhibition of mTOR with rapamycin (sirolimus) markedly slows cyst development and renal functional deterioration. Based on these promising results in animals we have designed and initiated the first randomized controlled trial (RCT) to examine the effectiveness, safety and tolerability of sirolimus to retard disease progression in ADPKD.

Method/design: This single center, randomised controlled, open label trial assesses the therapeutic effect, safety and tolerability of the mTOR inhibitor sirolimus (Rapamune) in patients with autosomal dominant polycystic kidney disease and preserved renal function. The primary outcome will be the inhibition of kidney volume growth measured by magnetic resonance imaging (MRI) volumetry. Secondary outcome parameters will be preservation of renal function, safety and tolerability of sirolimus.

Discussion: The results from this proof-of-concept RCT will for the first time show whether treatment with sirolimus effectively retards cyst growth in patients with ADPKD.

Trial registration: ClinicalTrials.gov NCT00346918.

Figures

Figure 1
Figure 1
Flow chart of SUISSE ADPKD study.

References

    1. Dalgaard OZ. Bilateral polycystic disease of the kidneys; a follow-up of two hundred and eighty-four patients and their families. Acta Med Scand Suppl. 1957;328:1–255.
    1. Hateboer N, v Dijk MA, Bogdanova N, Coto E, Saggar-Malik AK, San Millan JL, Torra R, Breuning M, Ravine D. Comparison of phenotypes of polycystic kidney disease types 1 and 2. European PKD1-PKD2 Study Group. Lancet. 1999;353:103–107. doi: 10.1016/S0140-6736(98)03495-3.
    1. Wilson PD. Polycystic kidney disease. N Engl J Med. 2004;350:151–164. doi: 10.1056/NEJMra022161.
    1. Harris PC, Rossetti S. Molecular genetics of autosomal recessive polycystic kidney disease. Mol Genet Metab. 2004;81:75–85. doi: 10.1016/j.ymgme.2003.10.010.
    1. Torra R, Badenas C, Darnell A, Nicolau C, Volpini V, Revert L, Estivill X. Linkage, clinical features, and prognosis of autosomal dominant polycystic kidney disease types 1 and 2. J Am Soc Nephrol. 1996;7:2142–2151.
    1. Franz KA, Reubi FC. Rate of functional deterioration in polycystic kidney disease. Kidney Int. 1983;23:526–529. doi: 10.1038/ki.1983.51.
    1. Grantham JJ, Torres VE, Chapman AB, Guay-Woodford LM, Bae KT, King BF, Jr., Wetzel LH, Baumgarten DA, Kenney PJ, Harris PC, Klahr S, Bennett WM, Hirschman GN, Meyers CM, Zhang X, Zhu F, Miller JP. Volume progression in polycystic kidney disease. N Engl J Med. 2006;354:2122–2130. doi: 10.1056/NEJMoa054341.
    1. Thomsen HS, Madsen JK, Thaysen JH, Damgaard-Petersen K. Volume of polycystic kidneys during reduction of renal function. Urol Radiol. 1981;3:85–89.
    1. Ruggenenti P, Remuzzi A, Ondei P, Fasolini G, Antiga L, Ene-Iordache B, Remuzzi G, Epstein FH. Safety and efficacy of long-acting somatostatin treatment in autosomal-dominant polycystic kidney disease. Kidney Int. 2005;68:206–216. doi: 10.1111/j.1523-1755.2005.00395.x.
    1. Morice MC, Serruys PW, Sousa JE, Fajadet J, Ban Hayashi E, Perin M, Colombo A, Schuler G, Barragan P, Guagliumi G, Molnar F, Falotico R. A randomized comparison of a sirolimus-eluting stent with a standard stent for coronary revascularization. N Engl J Med. 2002;346:1773–1780. doi: 10.1056/NEJMoa012843.
    1. Stallone G, Schena A, Infante B, Di Paolo S, Loverre A, Maggio G, Ranieri E, Gesualdo L, Schena FP, Grandaliano G. Sirolimus for Kaposi's sarcoma in renal-transplant recipients. N Engl J Med. 2005;352:1317–1323. doi: 10.1056/NEJMoa042831.
    1. Wahl PR, Serra AL, Le Hir M, Molle KD, Hall MN, Wuthrich RP. Inhibition of mTOR with sirolimus slows disease progression in Han:SPRD rats with autosomal dominant polycystic kidney disease (ADPKD) Nephrol Dial Transplant. 2006;21:598–604. doi: 10.1093/ndt/gfi181.
    1. Wu M, Wahl PR, Le Hir M, Waeckerle-Men Y, Wuthrich RP, Serra AL. Everolimus retards cyst growth and preserves kidney function in a rodent model for polycystic kidney disease . Kidney Blood Press Res. 2007;30:253–259. doi: 10.1159/000104818.
    1. Tao Y, Kim J, Schrier RW, Edelstein CL. Rapamycin markedly slows disease progression in a rat model of polycystic kidney disease. J Am Soc Nephrol. 2005;16:46–51. doi: 10.1681/ASN.2004080660.
    1. Shillingford JM, Murcia NS, Larson CH, Low SH, Hedgepeth R, Brown N, Flask CA, Novick AC, Goldfarb DA, Kramer-Zucker A, Walz G, Piontek KB, Germino GG, Weimbs T. From the Cover: The mTOR pathway is regulated by polycystin-1, and its inhibition reverses renal cystogenesis in polycystic kidney disease. Proc Natl Acad Sci U S A. 2006;103:5466–5471. doi: 10.1073/pnas.0509694103.
    1. Farmer KC. Methods for measuring and monitoring medication regimen adherence in clinical trials and clinical practice. Clin Ther. 1999;21:1074–90; discussion 1073. doi: 10.1016/S0149-2918(99)80026-5.
    1. Osterberg L, Blaschke T. Adherence to medication. N Engl J Med. 2005;353:487–497. doi: 10.1056/NEJMra050100.
    1. SUISSE ADPKD Study
    1. Ravine D, Gibson RN, Walker RG, Sheffield LJ, Kincaid-Smith P, Danks DM. Evaluation of ultrasonographic diagnostic criteria for autosomal dominant polycystic kidney disease 1. Lancet. 1994;343:824–827. doi: 10.1016/S0140-6736(94)92026-5.

Source: PubMed

Sponsor e collaboratori

Condizioni mediche

Interventi farmacologici

3
Sottoscrivi