European Alport Therapy Registry - European Initiative Towards Delaying Renal Failure in Alport Syndrome

Study Overview
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Brief Summary
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The hereditary type IV collagen disease Alport syndrome inevitably leads to end-stage renal disease. Currently there are no therapies known to improve outcome. Our non-interventional, observational study investigates, if medications such as ACE-inhibitors can (1) delay time to dialysis and (2) improve life-expectancy within three generations of Alport-families in Europe.

Detailed Description
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Early diagnosis in children with Alport syndrome (AS) with isolated hematuria opens a window of opportunity for early intervention. Currently there are no causal therapeutic options which are proven to delay renal failure in AS. ACE-inhibition (ACEi) has been shown to reduce proteinuria in Alport patients and to delay renal failure in Alport-mice suggesting it may be of value as an effective treatment to delay renal failure in humans. To test this we established the European Alport Registry to collect data over several generations of Alport families across Europe. Small children with AS first develop microscopic hematuria, proceeding to microalbuminuria, overt proteinuria, impaired renal function and end up with end stage renal disease. These different steps of disease enabled us to assess if earlier introduction of ACE-inhibition at earlier degrees of disease is more effective than later therapy in delaying the time to dialysis and improving life-expectancy. Heterozygous COL4A3/COL4A4 mutations result in the phenotype familial benign hematuria or thin basement membrane nephropathy (TBMN). Affected subjects typically present with hematuria. Having longtime been regarded as benign familial hematuria, those patients might have an increased risk to develop severe renal impairment - comparable to the findings in female XLAS carriers (see above). TBMN is not a rare disease, as at least 1% of the population is affected. For the first time, the present study compares the risk of renal impairment, end stage renal disease and premature death in between heterozygous carriers of XLAS and of ARAS mutations. Additionally, the nephroprotective effect of RAAS-blockade in patients with heterozygous Alport-mutations is evaluated.

Official Title
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European Alport Therapy Registry - European Initiative Towards Delaying Renal Failure in Alport Syndrome: Current and Novel Therapies

Conditions
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Alport Syndrome, Hereditary Kidney Disease, Pediatric Kidney Disease, Thin Basement Membrane Disease, Familial Benign Hematuria

Intervention / Treatment
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* Drug: ACE-inhibitor
* Drug: AT1-inhibitor
* Drug: HMG-Coenzyme inhibitor (statin)
* Drug: Spironolactone
* Drug: Paricalcitol
* Drug: SGLT2 inhibitor


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria/ Exclusion Criteria: The diagnosis of Alport syndrome (AS) was proven by kidney biopsy or mutation analysis (or both). Patients were included if they were affected males with X-linked AS or patients with genetically proven homozygous autosomal AS. Patients were excluded if they did not give informed consent or the diagnosis was suspected but not confirmed. The diagnosis of the heterozygous status was proven by (1) mutation analysis or (2) kidney biopsy plus genetic consultation for decision in between XLAS or ARAS inheritance (including a conclusive genealogic tree and/or linkage analysis). Patients were excluded if they were affected males with XLAS or patients with genetically proven homozygous ARAS. Patients were excluded if they did not give informed consent or the diagnosis was suspected but not confirmed or if they donated a kidney (living donor to affected family member).
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| no-T: untreated patients<br>untreated patients, typically uncles or grandfathers of present patients. No Intervention (means no therapy until CKD stage V, on renal replacement therapy) | |
| T-III: late therapy in patients<br>patients treated with RAAS-Blockade after onset of renal failure (GFR below 60 ml/min) (starts at patients with CKD stages III and IV). | Drug: ACE-inhibitor<br>* observational study!<br>* Other names: Ramipril;Drug: AT1-inhibitor<br>* observational study!<br>Drug: HMG-Coenzyme inhibitor (statin)<br>* observational study!<br>Drug: Spironolactone<br>* observational study!<br>Drug: Paricalcitol<br>* observational study!<br>Drug: SGLT2 inhibitor<br>* observational study!<br>|
| T-II: early therapy in patients<br>therapy starts at patients with proteinuria >0.3 g/day or per gCreatinine | Drug: ACE-inhibitor<br>* observational study!<br>* Other names: Ramipril;Drug: AT1-inhibitor<br>* observational study!<br>Drug: HMG-Coenzyme inhibitor (statin)<br>* observational study!<br>Drug: Spironolactone<br>* observational study!<br>Drug: Paricalcitol<br>* observational study!<br>Drug: SGLT2 inhibitor<br>* observational study!<br>|
| T-I: very early tharpy in patients<br>starts at patients with microhematuria only (usually at birth) or microalbuminuria (30-300 mg protein per day or per gCreatinine in children). | Drug: ACE-inhibitor<br>* observational study!<br>* Other names: Ramipril;Drug: AT1-inhibitor<br>* observational study!<br>Drug: HMG-Coenzyme inhibitor (statin)<br>* observational study!<br>Drug: Spironolactone<br>* observational study!<br>Drug: Paricalcitol<br>* observational study!<br>|
| no therapy in heterozygous carriers<br>heterozygous carriers without therapy | |
| therapy in heterozygous carriers<br>heterozygous carriers with RAAS-blockade | Drug: ACE-inhibitor<br>* observational study!<br>* Other names: Ramipril;Drug: AT1-inhibitor<br>* observational study!<br>Drug: HMG-Coenzyme inhibitor (statin)<br>* observational study!<br>Drug: Spironolactone<br>* observational study!<br>Drug: SGLT2 inhibitor<br>* observational study!<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| end stage renal disease | Age at onset of end stage renal failure | unlimited | 
| life-expectancy | life-expectancy of patients and carriers | unlimited | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| proteinuria after initiation of ACE-inhibitor-therapy |  | unlimited | 
| proportion of patients with a clinical diagnosis of hypertension |  | unlimited | 
| proportion of patients experiencing side effects from ACE-inhibitors | defined as acute renal failure (doubling of serum-creatinine), angioedema, hyperkalemia >5.0 mmol/l, dry cough, symptomatic hypotension (orthostatic collapse) and others, and death from all causes. | unlimited | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Alport syndrome, thin basement membrane disease, familial benign hematuria