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					Effects of Vitamin E administration in
 adolescents and young adults with
type I diabetes and microalbuminuria


                Francesco Chiarelli
   Department of Paediatrics, University of Chieti
                            Background
 Vitamin E is a well known antioxidant agent.

 The administration of high doses of Vitamin E reduces the morbidity and
mortality in patients with coronary heart disease (Stephens et al, Lancet 1996).

 In patients with type I diabetes, renal failure is a major complication with a high
rate of mortality.

 Microalbuminuria is reliable marker of incipient diabetic nephropathy (Mogensen et
al, Diabetes 1990).

 Products of glycooxidation and lipid-oxidation are increased in glomeruli of
patients with type II diabetes and clinical proteinuria (Horie et al, J Clin Invest 1997).

 An unbalanced oxidant/antioxidant status and oxidant sensitive cytokine
activation could play a role in the pathogenesis of early diabetic nephropathy.

 A recent study shows that oral vitamin E (1800 U/day) treatment seems to
normalise retinal hemodynamic and renal function (Bursell et al, Diabetes Care 1999),
while different authors could not document a benefit in protecting plasma LDL from
oxidative damage (Astley et al, Diabetes Care 1999).
Randomised placebo controlled cross-
            over study

Primary objective

is to determine whether the administration of high doses of
vitamin E is able to induce a reduction in persistent
microalbuminuria in patients with type 1 diabetes.

Secondary objective
is to determine whether the administration of high doses
of vitamin E is able to induce a reduction in markers of
oxidative stress and inflammatory products in patients
with type 1 diabetes.
                   Inclusion criteria
 Duration of 5 years of type I diabetes.

 15-30 years of age, Tanner IV-V.

 C-peptide negative.

 Persistent microalbuminuria (AER>20mcg/min in two out of
three consecutive overnight urine samples taken over a period
of 6 months).

 Intensified insulin regimen (3 or more insulin injections, or pump
therapy).

 HbA1c >7.5% and < 9%.

 Diet with a normal protein content (15-20% of total energy intake).
                Exclusion criteria
 Increased blood pressure (BP>90th P° or 135/85 mmHg).


 Incipient renal failure (creatininaemia<120mmol/L).


 Other chronic disease (including eating disorders).


 Diabetic neuropathy.


 Preproliferative or proliferative retinopathy.


 Vitamin supplements or drugs with antioxidant activity.

 Vegetarian diet.
                                Study Design
Run-in                               Period-1                                       Period-2
          Randomisation                                               wash out (4 weeks)
                                                                         cross-over
                            Vitamin E 600 mg/day



                                      Placebo

 -4            0       +8                     + 16                   + 24                   weeks
Urines       Urines    Urines                 Urines                 Urines

HbA1c                  HbA1c                  HbA1c                  HbA1c

                       Lipids                 Lipids                 Lipids
Lipids


C-Pep                  Bld spare              Bld spare              C-Pep
Bld spare              Amp BP                 Amp BP                 Bld spare
GFR                    Oxidative Indexes      Oxidative Indexes      GFR
Amp BP                 Inflammatory Indexes   Inflammatory Indexes   Amp BP
R Photo                                                              R Photo
Oxidative Indexes                                                    Oxidative Indexes
Inflammatory Indexes                                                 Inflammatory Indexes
                       Study days
 Normocaloric and normoproteic diet.

 Overnight collections will be performed on three consecutive days.
The overnight collections will not be performed in case of:

          severe hypoglycaemic episodes or hyperglycaemia

          urinary tract infection

         menstruation in girls

 On the third day the patient will visit the respective outpatient clinic for
a routine visit for:
          weight
          BP (random zero or 3 consecutive measurements)

          physical examination

          renal function (GFR with inulin test or creatinine clearance)

          retinal photography
          one single fasting blood sample (40cc).
                        Laboratory
 Microalbuminuria will be determined by radioimmunoassay.

 HbA1c will be determined by means of High Pressure Liquid
Chromatography (HPLC).
 Markers of oxidative stress studied:
            Vitamin E measured in plasma and on LDL

            LDL content of MDA

            Florescin product of lipid peroxidation (FPLPs)

            Lag phase

 Inflammatory indexes determined by ELISA:
            monocyte chemoactivated protein 1 (MSPC-1)

            IL-1
            TNF-
            CD40L
            ROS production
                  Statistical Analysis
 Comparison of differences between groups will be analysed by
Wilcoxon rank testing.

 ANOVA will be used to determine changes over time.


 Linear correlation will be carried out between AER and plasma level of
Vitamin E.


 Multifactorial regression analysis will be performed for testing
indipendence.


                Power Calculation
A total of 50 patients will enable us to detect a reduction in 20% of the
subject with microalbuminuria at a significant level of 95% at a 5% level.
                  Statistical Analysis
 Comparison of differences between groups will be analysed by
Wilcoxon rank testing.

 ANOVA will be used to determine changes over time.


 Linear correlation will be carried out between AER and plasma level of
Vitamin E.


 Multifactorial regression analysis will be performed for testing
indipendence.


                Power Calculation
A total of 50 patients will enable us to detect a reduction in 20% of the
subject with microalbuminuria at a significant level of 95% at a 5% level.
   Effects of angiotensin II receptor
  antagonists on the progression of
incipient nephropathy in adolescents
and young adults with type 1 diabets


               Francesco Chiarelli
  Department of Paediatrics, University of Chieti
                            Background
 In patients with type I diabetes, renal failure is a major complication with a high
rate of mortality.
 Products of glycooxidation and lipid-oxidation are increased in glomeruli of
patients with type II diabetes and clinical proteinuria (Horie et al, J Clin Invest 1997).

 An unbalanced oxidant/antioxidant status and oxidant sensitive cytokine
activation could play a role in the pathogenesis of early diabetic nephropathy.

 Due to the known reno-protective effect associated with antihypertensive action,
drugs affecting the renin-angiotensin system such as the angiotensin converting
enzym inhibitors have become first choice for treatment (Mogensen et al, BMJ 2000).

Alternative pathways to the ACE for angiotensin II might be more important in
causing tissue damage and angiotensin II receptor antagonists might therefore
have a more direct effect on activated inflammatory cytokines and oxidative stress
(Owen et al, J Immunol 1998).
 The detection of abnormal urinary albumin excretion represents a surrogate
marker of the underlying renal structural damage and an improvement might not
necessarily reflect the improvement of prior histological changes.

 Only limited data on the effect of ACE-inhibitors performing serial renal biopsies
are available and the results are inconclusive (Gulman et al, Virchows Arch 2001).
Randomised placebo controlled double
          blinded study

Primary objective
is to determine whether the administration of ACE receptor
antagonist is able to revert renal glomerular lesions
established by renal biopsy in patients with type 1 diabetes.

Secondary objective
is to determine whether the administration of ACE receptor
antagonist is able to induce a reduction in markers of
oxidative stress and inflammatory products in patients
with type 1 diabetes.
                   Inclusion criteria

 Duration of 5 years of type I diabetes.

 20-30 years of age, Tanner V.

 C-peptide negative.

 Persistent microalbuminuria (AER>20mcg/min in two out of
three consecutive overnight urine samples taken over a period
of 6 months).

 Intensified insulin regimen (3 or more insulin injections, or pump
therapy).

 HbA1c >7.5% and < 9%.
                Exclusion criteria
 Increased blood pressure (BP>90th P° or 135/85 mmHg).


 Incipient renal failure (creatininaemia<120mmol/L).


 Other chronic disease (including eating disorders).


 Diabetic neuropathy.


 Preproliferative or proliferative retinopathy.


 Vitamin supplements or drugs with antioxidant activity.
                                Study Design
Run-in
     Randomisation

              Group A              Angiotensin II receptor antagonist


              Group B
                                   Placebo

          0                          2 years                             5 years
         Renal biopsy                Renal biopsy             Renal biopsy

         HbA1c                       HbA1c                    HbA1c

                                     Urines                   Urines
         Urines

                                                              Bld spare
         C-Pep                      Bld spare
                                                              GFR
         Bld spare                  GFR
                                                              Amp BP
         GFR                        Amp BP
                                                              R Photo
         Amp BP                     R Photo
                                                              Oxidative Indexes
         R Photo                    Oxidative Indexes
                                                              Inflammatory Indexes
         Oxidative Indexes          Inflammatory Indexes
         Inflammatory Indexes
                Kidney Biopsy (1)
 Tissue will be examined in order to ensure adequate numbers of glomeruli.
 Electron microscopy:
          Glomerular cell number
          Slit pore length density
          Surface density of peripheral of the glomerular basement membrane
          Foot process width
          Glomerular basement membrane width

          Mesangial cell and matrix number
          Tubular basement membrane

 Light microscopy:
          Glomerular volume
          Volume fraction of cortex

          Volume fraction of cortex

          Index of arteriolar hylinosis
          Scleortic gloeruli
              Kidney Biopsy (1)

                                   Immunofluorescence:
 Immunohystochemistry:
    Metalproteinasis (MM5, MM9)         CD68+

    Collagenasis IV                     HLA-DR+

    Fibronectin                         CD3+

    Lamin                               Cox-2

    Nephrin                             MCP-1

                                        CD40L

                                        MMP-9

                                        MMP-2
                        Laboratory
 Microalbuminuria will be determined by radioimmunoassay.

 HbA1c will be determined by means of High Pressure Liquid
Chromatography (HPLC).

 Markers of oxidative stress studied:

            LDL content of MDA

            Florescin product of lipid peroxidation (FPLPs)

            Lag phase

 Inflammatory indexes determined by ELISA:
            monocyte chemoactivated protein 1 (MSPC-1)

            IL-1
            TNF-
            CD40L
            ROS production
                  Statistical Analysis
 Comparison of differences between groups will be analysed by
Wilcoxon rank testing.

 ANOVA will be used to determine changes over time.


 Linear correlation will be carried out between AER and plasma level of
Vitamin E.


 Multifactorial regression analysis will be performed for testing
indipendence.


                     Consideration
A possible progression of the nephropathy is of particular concern in the
placebo group as a progression might require treatment and determine
drop out. In this case the patient will be invited to perform a renal biopsy.

				
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