Effects of an Intensified Treatment With ACE-I,ATA II and Statins in Alport Syndrome
Condition: Alport Syndrome
MeSH terms: Nephritis, Hereditary; Syndrome
Study type: Interventional
Phase: Phase 2

Summary: 
      Alport syndrome (AS) represents a form of progressive hereditary nephritis in which the
      genetic defect resides in the synthesis of one of several subunits of type IV collagen, the
      predominant constituent of basement membranes in renal glomeruli. Renal impairment occurs
      with time and severe renal failure with hypertension and uremia represent the end stage of
      the disease, even if a high variability in the rate of progression is described.Males are
      usually affected by a progressive form of the disease. Affected females with X-linked
      syndrome usually have a good prognosis with a mild renal impairment. The disease is also
      associated to a sensor neural deafness which can occur in approximately half of the patient
      affected and usually correlates with renal impairment. No definite treatment exists in order
      to delay the time of dialysis or a kidney transplant. Many studies showed that Angiotensin
      converting enzyme (ACE) inhibitors slow glomerular filtration rate (GFR) decline and limit
      progression to end stage renal disease (ERDS) and dialysis in several chronic nephropathies
      associated with proteinuria. The combination of ACE-I with Angiotensin II receptor
      antagonists may reduce proteinuria more effectively than the two drugs alone. Moreover the
      addition of statins may synergize the antiproteinuric effects of ACE-I and ATAII antagonists
      in experimental models of chronic renal diseases.

      The purpose of this study is to evaluate the effect of a standardized multimodal
      nephroprotection intervention (Remission Clinic) in Alport patients with renal involvement.
    

Detailed description: 
      Alport syndrome (AS) represents a form of progressive hereditary nephritis in which the
      genetic defect resides in the synthesis of one of several subunits of type IV collagen, the
      predominant constituent of basement membranes in glomeruli, eye, cochlea. From a genetical
      point of view, the disease is quite heterogeneous, since we have X-linked, autosomal
      recessive and autosomal dominant variants of the syndrome. In most cases (about 80%) the
      model of inheritance is X-linked and the affected patients are males. Here the mutation stays
      on X-chromosome in a gene codifying for alpha-5(IV). In about 15% of patients the inheritance
      is autosomal recessive, with a severe disease both in males and females. The involved genes
      here are located on chromosome 2 and codifying respectively for alpha-3(IV) and alpha-4(IV)
      chains. In a 5% the model of inheritance is autosomal dominant and here the deterioration of
      renal function usually occurs more slowly.

      Clinical manifestations include microscopic hematuria as the first finding, which can also
      became gross hematuria (episodes during upper respiratory infections) or manifest as
      intermittent (heterozygous females). Another sign is proteinuria of various degrees. It may
      be from insignificant, described in heterozygous females, or a progressive proteinuria
      (recessive or X-linked disease). It is evident from clinical studies of Alport patients that
      a persistent massive proteinuria, inducing a progressive interstitial fibrosis, indicates a
      very poor prognosis. The presence of glomerular podocytes has been described in urinary
      sediments of patients with renal diseases, including AS and recent data suggest that
      podocyturia could act as a marker for estimating the severity of active glomerular injury and
      as a predictor of disease progression. Renal impairment occurs with time and severe renal
      failure with hypertension and uremia represent the end stage of the disease, even if an high
      variability in the rate of progression is described. The prognosis is variable. Males are
      usually affected by progressive form of disease. Affected females with X-linked syndrome
      usually have a good prognosis with a mild renal impairment. Some females evolve in a
      progressive nephritis. The disease is also associated to a sensorineural deafness which can
      occur in approximately half of the patient affected and usually correlates with renal
      impairment. Many studies showed that angiotensin converting enzyme (ACE) inhibitors slow
      glomerular filtration rate (GFR) decline and limit progression to end stage renal disease
      (ERDS) and dialysis in several chronic nephropathies. ACE inhibitors delay renal fibrosis
      both by an hemodynamic mechanism (reduction of the intraglomerular hypertension, glomerular
      hyperfiltration and associated proteinuria) and a non-hemodynamic mechanism (decrease of
      angiotensin II, a potent inducer of TGF-β release which is a fibrogenic cytokine).

      ACE inhibitors given to COL4A3 knockout mouse (a model for autosomal-recessive AS) during
      pre-symptomatic disease, markedly delayed the onset of proteinuria, progressive renal damage
      and uremia. Conversely the same treatment did not improve renal outcome in this mouse model
      if fibrosis and impairment of renal function was already present. These results are in
      agreement with the findings that ACE inhibitor have beneficial effects against proteinuria,
      renal function deterioration and survival in Samoyed dogs, a model for X-linked hereditary
      nephropathy closely mimicking human AS.

      Moreover recent clinical data suggest that even in young patients affected by AS a decrease
      in proteinuria and a stabilization in renal function result from the use of ACE inhibition.

      The combination of ACE-I with ATAII antagonists may reduce proteinuria more effectively than
      the two drugs alone. Moreover the addition of statins may synergize the antiproteinuric
      effects of ACE-I and ATAII antagonists in experimental models of chronic renal diseases.
      Statins given with or without inhibitors of the renin-angiotensin-system have an additive
      effect on reducing proteinuria also in humans.

      The purpose of this study is to evaluate the effects of a multimodel treatment including the
      integrated use of ACE inhibitors (ACE-I), Angiotensin II antagonists (ATA), non
      dihydropyridinic calcium channel blockers (CCBS) and statins in AS and renal involvement.

      Aims of the study Primary To evaluate the effect of a standardized multimodal
      nephroprotection intervention (Remission Clinic) on overnight urine albumin excretion rate
      (UAE) in Alport patients with renal involvement Secondary

        1. To evaluate the effect of the above treatment on:

             -  regression from macro to micro or normoalbuminuria

             -  regression from micro to normoalbuminuria

             -  regression from high-normal albuminuria to low-normal albuminuria

             -  urinary albumin/creatinine ratio

             -  systolic/diastolic blood pressure

             -  urinary podocyte excretion

             -  albumin-IgG-IgM fractional clearances

        2. To assess treatment tolerability
    

Intervention name(s): ACE I, ATA II and Statins; Benazepril, Valsartan and Fluvastatin
Intervention type(s): Drug; Drug
Intervention description(s): Patients will be given a low dose of Benazepril, 10 mg/die,that, if tolerated, will be up-titrated, after a week,to 20 mg/day.
Patients will be given Valsartan, 80 mg/die,up-titrated after a week to 160 mg/die. Fluvastatin will be started at 40 mg/die.If tolerated, will up-titrated to 80 mg/die. In case of liver, muscular or renal toxicity, fluvastatin will be back-titrated to 40 mg or withdrawn as deemed appropriate.
Intervention MeSH terms: Valsartan; Benazepril
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment