Study Results
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Basic Information
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COMPLETED
37 participants
OBSERVATIONAL
2013-10-31
2015-07-31
Brief Summary
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Detailed Description
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Besides the well-known metabolic and cardiovascular effects, it has been recently shown that statins increase the plasma membrane expression of the renal water channels Aquaporin 2 (AQP2). Water reabsorption in the kidney connecting tubule and collecting duct is regulated by the antidiuretic hormone arginine vasopressin (AVP), which promotes plasma membrane expression of the water channe aquaporin 2 (AQP2), the rate-limiting step controlling reabsorption of water, thus urine concentration, in this segment of the nephron. The investigators reported a number of evidences showing that statins accumulate AQP2 at the apical membrane of collecting duct cells by a AVP-independent mechanism. The effect of statins on AQP2 is independent of classical cholesterol homeostasis but rather depends on depletion of mevalonate-derived intermediates of cholesterol synthetic pathways, i.e. isoprenoid intermediates, including farnesylpyrophosphate (FPP) and geranylgeranylpyrophosphate (GGPP).
Water balance disorders are often associated with defects of AQP2 trafficking. Nephrogenic Diabetes Insipidus (NDI) is characterized by the inability of the kidney to respond to AVP stimulation and is caused by either mutations in AQP2 or vasopressin type-2 receptor (AVPR2) genes. Mutations in the AVPR2 gene lead to X-linked NDI (X-NDI). This cause of 90% of all diagnosed congenital NDI cases.
Conventional treatment of X-NDI patients consists in low-sodium, low-protein diet and the administration on thiazide diuretics sometimes in combination with indomethacin or amiloride. Although these drugs cause some relief of X-NDI symptoms, they most often do not eliminate them. Due to the partial beneficial effect of conventional treatments, much effort has been spent in the past years to uncover new and alternative methods to induce antidiuresis in X-NDI patients.
In this regard, the investigators recently reported that statins, in particular fluvastatin, accumulate AQP2 at the apical membrane of collecting duct cells by a AVP-independent mechanism and increase water reabsorption in both wild type and X-NDI mice.
The effect of statins on AQP2 trafficking in humans, however, deserves further investigation, also considering the potential efficacy of statins in patients with X-NDI. This was the reason to embark on the present study in which the investigators monitored the time-dependent effects of statin therapy on the urine excretion of AQP2, diuresis and urine osmolality in a cohort of hypercholesterolemic subjects initiating simvastatin therapy for three months. Two other groups of patients serve as controls: patients already on statin treatment and patients choosing to undergo an initial program with a standard hypolipidemic "mediterranean" style diet.
Conditions
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Study Design
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COHORT
PROSPECTIVE
Study Groups
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Naïve-S
Patients with hypercholesterolemia starting statin treatment for primary or secondary prevention of cardiovascular diseases.
No interventions assigned to this group
ONC-S
Patients with hypercholesterolemia who had been treated with statin for at least one year and continued their previous therapy during the study period
No interventions assigned to this group
Naïve-MC
Patients with mild hypercholesterolemia either refusing initial statin treatment or intolerant to standard statin treatment and starting with monacolin K
No interventions assigned to this group
Naïve-Diet
Patients refusing an initial pharmacologic treatments and choosing the hypolipidic diet
No interventions assigned to this group
Eligibility Criteria
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Inclusion Criteria
* age 40 to 75 years
* estimated 10-year ASCVD risk ≥7.5%
Exclusion Criteria
* blood hypertension
* concomitant use of diuretics or other drugs interfering with simvastatin
40 Years
75 Years
ALL
No
Sponsors
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University of Bari
OTHER
Responsible Party
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piero portincasa
Professor of Medicine, PhD
Principal Investigators
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Piero Portincasa
Role: PRINCIPAL_INVESTIGATOR
University of Bari Medical School
Locations
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Department of Biomedical Sciences Human Oncology - Clinica Medica "A. Murri"
Bari, , Italy
Countries
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References
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Greenwood J, Steinman L, Zamvil SS. Statin therapy and autoimmune disease: from protein prenylation to immunomodulation. Nat Rev Immunol. 2006 May;6(5):358-70. doi: 10.1038/nri1839.
Pisitkun T, Shen RF, Knepper MA. Identification and proteomic profiling of exosomes in human urine. Proc Natl Acad Sci U S A. 2004 Sep 7;101(36):13368-73. doi: 10.1073/pnas.0403453101. Epub 2004 Aug 23.
Valenti G, Laera A, Pace G, Aceto G, Lospalluti ML, Penza R, Selvaggi FP, Chiozza ML, Svelto M. Urinary aquaporin 2 and calciuria correlate with the severity of enuresis in children. J Am Soc Nephrol. 2000 Oct;11(10):1873-1881. doi: 10.1681/ASN.V11101873.
Kanno K, Sasaki S, Hirata Y, Ishikawa S, Fushimi K, Nakanishi S, Bichet DG, Marumo F. Urinary excretion of aquaporin-2 in patients with diabetes insipidus. N Engl J Med. 1995 Jun 8;332(23):1540-5. doi: 10.1056/NEJM199506083322303.
Valenti G, Laera A, Gouraud S, Pace G, Aceto G, Penza R, Selvaggi FP, Svelto M. Low-calcium diet in hypercalciuric enuretic children restores AQP2 excretion and improves clinical symptoms. Am J Physiol Renal Physiol. 2002 Nov;283(5):F895-903. doi: 10.1152/ajprenal.00354.2001.
Wade JB. Statins affect AQP2 traffic. Am J Physiol Renal Physiol. 2011 Aug;301(2):F308. doi: 10.1152/ajprenal.00248.2011. Epub 2011 May 11. No abstract available.
Li W, Zhang Y, Bouley R, Chen Y, Matsuzaki T, Nunes P, Hasler U, Brown D, Lu HA. Simvastatin enhances aquaporin-2 surface expression and urinary concentration in vasopressin-deficient Brattleboro rats through modulation of Rho GTPase. Am J Physiol Renal Physiol. 2011 Aug;301(2):F309-18. doi: 10.1152/ajprenal.00001.2011. Epub 2011 Apr 20.
Grunfeld JP, Rossier BC. Lithium nephrotoxicity revisited. Nat Rev Nephrol. 2009 May;5(5):270-6. doi: 10.1038/nrneph.2009.43.
Frokiaer J, Marples D, Knepper MA, Nielsen S. Bilateral ureteral obstruction downregulates expression of vasopressin-sensitive AQP-2 water channel in rat kidney. Am J Physiol. 1996 Apr;270(4 Pt 2):F657-68. doi: 10.1152/ajprenal.1996.270.4.F657.
Marples D, Frokiaer J, Dorup J, Knepper MA, Nielsen S. Hypokalemia-induced downregulation of aquaporin-2 water channel expression in rat kidney medulla and cortex. J Clin Invest. 1996 Apr 15;97(8):1960-8. doi: 10.1172/JCI118628.
Bustamante M, Hasler U, Leroy V, de Seigneux S, Dimitrov M, Mordasini D, Rousselot M, Martin PY, Feraille E. Calcium-sensing receptor attenuates AVP-induced aquaporin-2 expression via a calmodulin-dependent mechanism. J Am Soc Nephrol. 2008 Jan;19(1):109-16. doi: 10.1681/ASN.2007010092. Epub 2007 Nov 21.
Procino G, Carmosino M, Tamma G, Gouraud S, Laera A, Riccardi D, Svelto M, Valenti G. Extracellular calcium antagonizes forskolin-induced aquaporin 2 trafficking in collecting duct cells. Kidney Int. 2004 Dec;66(6):2245-55. doi: 10.1111/j.1523-1755.2004.66036.x.
Moeller HB, Rittig S, Fenton RA. Nephrogenic diabetes insipidus: essential insights into the molecular background and potential therapies for treatment. Endocr Rev. 2013 Apr;34(2):278-301. doi: 10.1210/er.2012-1044. Epub 2013 Jan 29.
Patrick L, Uzick M. Cardiovascular disease: C-reactive protein and the inflammatory disease paradigm: HMG-CoA reductase inhibitors, alpha-tocopherol, red yeast rice, and olive oil polyphenols. A review of the literature. Altern Med Rev. 2001 Jun;6(3):248-71.
Bonfrate L, Procino G, Wang DQ, Svelto M, Portincasa P. A novel therapeutic effect of statins on nephrogenic diabetes insipidus. J Cell Mol Med. 2015 Feb;19(2):265-82. doi: 10.1111/jcmm.12422. Epub 2015 Jan 16.
Murer L, Addabbo F, Carmosino M, Procino G, Tamma G, Montini G, Rigamonti W, Zucchetta P, Della Vella M, Venturini A, Zacchello G, Svelto M, Valenti G. Selective decrease in urinary aquaporin 2 and increase in prostaglandin E2 excretion is associated with postobstructive polyuria in human congenital hydronephrosis. J Am Soc Nephrol. 2004 Oct;15(10):2705-12. doi: 10.1097/01.ASN.0000139689.94776.7A.
Procino G, Milano S, Carmosino M, Barbieri C, Nicoletti MC, Li JH, Wess J, Svelto M. Combination of secretin and fluvastatin ameliorates the polyuria associated with X-linked nephrogenic diabetes insipidus in mice. Kidney Int. 2014 Jul;86(1):127-38. doi: 10.1038/ki.2014.10. Epub 2014 Feb 12.
Procino G, Barbieri C, Carmosino M, Rizzo F, Valenti G, Svelto M. Lovastatin-induced cholesterol depletion affects both apical sorting and endocytosis of aquaporin-2 in renal cells. Am J Physiol Renal Physiol. 2010 Feb;298(2):F266-78. doi: 10.1152/ajprenal.00359.2009. Epub 2009 Nov 18.
Procino G. Fluvastatin Increases AQP2 Urine Excretion in a Dyslipidemic Patient with Nephrogenic Diabetes Insipidus: An In Vivo and In Vitro Study. Journal of Diabetes & Metabolism 2014; 5(7); 1000408
Other Identifiers
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MRAR08P011
Identifier Type: OTHER
Identifier Source: secondary_id
uAQP2/01
Identifier Type: -
Identifier Source: org_study_id
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