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
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
To assess treatment tolerability
