Use of Mucomyst to Ameliorate Oxidant Stress in Diabetics With Proteinuria
Condition: Diabetes; Proteinuria
MeSH terms: Proteinuria
Study type: Interventional

Summary: 
      The study will look at the effect of 30 days of treatment of 15 diabetics with proteinuria
      with N-acetylcysteine ( Mucomyst ) at a dose of 1 gm twice a day by mouth. The primary
      outcome that will be measured is change in the oxidant stress as measurable by changes in the
      serum level of isoprostane, Glutathione peroxidase, aconitase and Total oxidant stress.
      Secondary outcomes measured will be changes in proteinuria and kidney function as measured by
      spot urine pr/cr and estimated GFR by MDRD formula.
    

Detailed description: 
      Mucomyst (Acetylcysteine) for amelioration of diabetic nephropathy

      Hypothesis:

      Treatment with Mucomyst over several months will reduce the oxidant stress and thereby reduce
      the proteinuria and the progression of renal failure in patients with diabetic nephropathy.

      Rationale:

      Mucomyst or Acetylcysteine has now been found to be beneficial in ameliorating radio-contrast
      induced acute renal failure in several different studies (ref 1) The beneficial effects of
      Mucomyst is most likely due to its antioxidative properties. Oxidative stress plays a major
      role in diabetic complication especially in diabetic nephropathy.

      In a recent in vitro study Acetylcysteine ameliorated the deleterious effects of albumin on
      cultured renal proximal tubular epithelial cells. Murine proximal tubular cells were treated
      with albumin (30 mg/ml medium) for various lengths of time. The results showed that albumin
      could activate Stat1 and Stat5 within 15 min in proximal tubular cells. The activation of
      STATs was mediated mostly by Jak2 and required no protein synthesis. In addition, activation
      of Stat1 occurred even after neutralization of IFN- . The activation of STATs was inhibited
      by N-acetyl-L-cysteine, a precursor of glutathione and a reactive oxygen species (ROS)
      scavenger, and fluorescence-activated cell sorter analysis showed upregulation of
      intracellular ROS after albumin overloading, suggesting that albumin per se could generate
      ROS in proximal tubular cells. The activation of STATs occurred by way of the ROS generating
      system, and especially through the membrane-bound NADPH oxidase system. Reduced activities of
      glutathione peroxidase and catalase could also be responsible for the accumulation of
      intracellular ROS. Hence, not only the ROS generating system, but also the ROS scavenging
      system may contribute to the induction of ROS by albumin.

      N-acetylcysteine also may attenuate the course of hepatorenal syndrome, a renal
      vasoconstrictive response of indeterminate nature that develops during advanced liver
      failure. This effect, shown in experimental settings [9] and in a preliminary clinical report
      [10], could imply a better preservation of liver function. However, direct renal protective
      mechanisms may play a role also, considering the ubiquitous distribution of acylases that
      catalyze the deacetylation of NAC [11]. Indeed, recent studies suggest that NAC may increase
      intracellular glutathione and ameliorate renal ischemia-reflow injury [12-14], inferior vena
      cava-occlusion [15] or kidney damage from cis-platinum [16], cyclosporine [17], and other
      nephrotoxic insults [18, 19]. NAC has been reported recently to prevent radiocontrast
      nephropathy in high-risk patients [20]. These studies, conducted in a clinical trial without
      preliminary experiments in animals, underscore the safety of oral NAC administration.

      As stated above, the mechanism of NAC-related organ protection is primarily attributed to
      scavenging oxygen free radicals, either directly, or through increasing intracellular
      glutathione concentration [3, 4]. Indeed, decreased malonaldehyde production indicates an
      attenuation of membrane damage from oxygen-free radicals [3], but other protective mechanisms
      may play a role as well [21]. Improved local microcirculation may be a major potential
      NAC-related organ-protective mechanism. NAC was reported to augment papillary flow [22] and
      was found to improve renal vasodilation in response to acetylcholine [15]. Thus, perhaps some
      of the protective effects of NAC can be attributed to improved glomerular hemodynamics or to
      the prevention of hypoxic tubular damage via restoration of altered renal microcirculation.

      NAC ameliorates renal vasoconstriction, an effect that seems to be mediated by mechanisms
      other than prostaglandins and nitric oxide

      NAC had been safely used in a large group of ESRD patients for over one year ( 600 mg bid by
      mouth ) in a prospective randomized trial . The group treated with NAC had reduction in
      composite cardiovascular endpoints ( 18% vs 47%) ( Ref: Circulation2003,107: 992 . Tepel et
      al )

      Similarly in a RCt of Alzheimer patients NAC treatment for 6 months showed benefit in
      cognitive tasks in the treatment group. ( Ref: Neurology2001, 23: 57: Adair et al )

      Intravenous injection of NAC prior to dialysis increased the dialysis clearance of
      homocysteine and improved endothelial function in a group of ESRD patient ( Ref: Circulation
      2003, 109: 369; Scholze et al )

      NAC treatment was also found to have potentiating effect of the antihypertensive effects of
      ACE inhibitors in hypertensive patients ( Blood pressure 2002, 11:235; Barrios et al )

      In another RCT in an aging population, chronic treatment with NAC was seen to cause
      significant decrease in plasma TNF-alpha and improved the muscle strength. ( Ref: J Mol MED
      2003; 81: 118; Hauer et al.)

      Protocol:

      All patients with diabetes and proteinuria at any level will be eligible for the study.
      Patients who are on dialysis and who have known allergy to Mucomyst will be excluded

      Patients will get Mucomyst 1000 mg by mouth twice a day for 30 days. Urine and serum will be
      collected at the beginning, , at 15 and 30 days after starting Mucomyst and 30 days after
      stopping Mucomyst. Portions of the blood and urine will be frozen and mailed to a special lab
      to measure the chemicals that determine the level of oxidative stress. The particular
      chemicals that will be tested for are isoprostane in urine and isoprostane, aconitase,
      glutathione peroxidase and total serum antioxidant stress in the blood. The special tests
      will be done by Dr. Valyathan's lab . Locally we will test blood and urine for proteinuria
      and kidney Fx.

      .

      Data collection:

      Demographic information:

      Wt, BP at every visit:

      Med list rechecked at every visit:

      At every visit:

      Collection of blood for different measures of oxidant stress: serum will be frozen to be sent
      to Dr. Vallyathan's lab later.

      Blood for renal function test

      Spot urine protein/cr (quantitative proteinuria) and also for measuring isoprostane

      Outcome:

      The primary outcome will be the reduction in the measured oxidant stress markers in the serum
      such as isoprostane, glutathione peroxidase, aconitase, and total oxidant stress. Secondary
      outcome will be reduction in proteinuria and the change in kidney function during treatment
      with Mucomyst.
    

Intervention name(s): N-acetylcysteine(Mucomyst)
Intervention type(s): Drug
Intervention MeSH terms: Acetylcysteine; N-monoacetylcystine
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Oxidative stress; N-acetylcysteine; NAC; Isoprostane; Proteinuria; Diabetes; Mucomyst; albuminuria