Effect of Statin Treatment on Urinary AQP2 (uAQP2/01)
Condition: Hypercholesterolemia; Diabetes Insipidus
MeSH terms: Diabetes Insipidus; Hypercholesterolemia
Study type: Observational

Summary: 
      The purpose of this study is to test the hypothesis that the function and/or regulation of
      urinary aquaporin 2 in hypercholesterolemic humans is affected by standard statin therapy, as
      compared with diet alone
    

Detailed description: 
      Statins are the first-line recommended pharmacological therapy in patients with dyslipidemias
      and play a key role in both primary and secondary prevention of coronary heart disease. By
      decreasing plasma total and low-density lipoprotein cholesterol (LDL-C) concentrations,
      statins decrease the risks for atherosclerotic cardiovascular disease and associated
      morbidity and mortality. Statins occupy part of the active binding site of
      3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) and inhibit its enzymatic activity in the
      liver, a key step leading to the reduction of cellular sterol pool. Statins also have
      beneficial effects on the vascular wall by stabilizing the atherosclerotic plaques,
      ameliorating impaired endothelial function, and reducing vascular inflammation.

      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.
    

Observational model: Cohort
Time perspective: Prospective
Sampling method: Probability Sample
Study population: 
        Behavioral: diet Drug: statins, as required according to the ACC/AHA guidelines Diagnostic:
        anthropometric data, abdominal and carotid ultrasonography, serum (lipids, renal function)
        and urinary (AQP2, osmolality) dosages at enrollment and during a 3-months follow up (week
        0, 1, 4, 12)
      
Biospecimen description: 
      Blood analyses (serum lipids, creatininemia, glucose, bilirubin) Urines (creatininuria,
      urinary AQP2)