Ignite Creation Date:
2024-05-05 @ 4:45 PM
Last Modification Date:
2024-10-26 @ 9:24 AM
Study NCT ID:
NCT00309257
Status:
COMPLETED
Last Update Posted:
2023-04-04
First Post:
2006-03-30
Brief Title:
Effects of an Intensified Treatment With ACE-IATA II and Statins in Alport Syndrome
Sponsor:
Mario Negri Institute for Pharmacological Research
Organization:
Mario Negri Institute for Pharmacological Research
Study Overview
Official Title:
Effects of an Intensified Treatment With ACE-inhibitors Angiotensin II Receptor Antagonists and Statins in Alport Syndrome
Status:
COMPLETED
Status Verified Date:
2009-10
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief 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 describedMales 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
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-5IV 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-3IV and alpha-4IV 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 albumincreatinine ratio
systolicdiastolic blood pressure
urinary podocyte excretion
albumin-IgG-IgM fractional clearances
2 To assess treatment tolerability
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 albumincreatinine ratio
systolicdiastolic blood pressure
urinary podocyte excretion
albumin-IgG-IgM fractional clearances
2 To assess treatment tolerability
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None