Overview
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.
Description
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.
Eligibility
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).