The hereditary type IV collagen disease Alport syndrome leads to kidney failure early in life. Currently there are no specific medications approved for treatment, however, several therapies have been evaluated preclinically and could improve outcome. For that reason, this non-interventional, observational study investigates, if medications (1) delay disease progression; (2) delay time to kidney failure; (3) improve life-expectancy compared to untreated patients (relatives). This observational study started in 2006 as an European registry. Since 2019, this registry has been expanded to "Alport XXL" via the International Alport Alliance as a global effort across all continents. From 2020 on to present, "Alport XXL" has a special focus on the outcomes of early therapy in young patients on ACE-inhibitors vs. Angiotensin-receptor blockers vs. their combination.

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

Alport Syndrome

Hereditary Kidney Disease

Pediatric Kidney Disease

Thin Basement Membrane Disease

Familial Benign Hematuria

Early diagnosis in children with Alport syndrome (AS) with isolated hematuria opens a "window of opportunity" for early intervention. In the Alport mouse-model, this early intervention with the ACE-inhibitor Ramipril let to a delay of kidney failure by 111%. In order to observe treatment approaches for AS in humans, this registry has been established in 2006 to collect data over several generations of Alport families across Europe. In the meantime, this registry has been expanded to "Alport XXL" via the International Alport Alliance as a global effort across all continents.

Small children with AS first develop microscopic hematuria (stage 0), proceeding to microalbuminuria (stage I), overt proteinuria (stage II), impaired kidney function (stage III) and finally can end up with kidney failure (stage IV), leading to impaired quality of life and premature death (stage V). This registry uses these stages to assess if earlier initiation of medications such as ACE-inhibition at earlier stages of disease is more effective than later therapy in delaying the time to disease progression (doubeling or tripeling of albuminuria), delaying loss of estimated glomerular filtration rate (eGFR), and if therapy improves life-expectancy.

Untreated children with autosomal-recessive AS, digenic AS, and boys with X-linked AS typically all develop kidney failure early in life. Untreated girls with X-linked AS have a 30-40% risk of kidney failure, typically later in life (40 years or older). Untreated heterozygous patients with COL4A3/COL4A4 variants typically have a less severe phenotype (in former times also called "familial benign hematuria" or "thin basement membrane nephropathy" (TBMN)) and a 1-2% risk of kidney failure.

Several interim results of this registry have been published since 2012.

Alport XXL is designed and conducted as strictly observational, non-interventional data acquisition with prospective (and in parts retrospective) data analysis. Young patients with AS in disease stages 0,I,II from all over the world are included. The renewed version from 2021 has been re-approved by the Ethics Committee of the University Medical Center Göttingen as "Alport XXL", a further development of the former European Alport Therapy Registry (AZ 10/11/06). "Alport XXL" registry and data storage are in conformity with Good Clinical Practice guidelines.

ICH-GCP-conform patient information and data exchange is secured by data transfer and cooperation agreements between all international trial centers and the coordinating principal investigator at University Medical Center Goettingen. At baseline, data collection including retrospective data is performed using a standardized, ICH-GCP-conform and pseudonymized questionnaire assessing age, sex, weight, height, mode of inheritance (X-linked, autosomal, compound heterozygous/homozygous, number of missense variants), family history, albumin in 24-hour or spontaneous urine, serum-creatinine, RAS-blockade with preparation and dose. Follow-up visits include same data than baseline plus blood-pressure, smoking-status, serum-potassium, eGFR, hearing loss and eye involvement, other symptoms such as leiomyomatosis, comorbidities and adverse events (adverse events of special interest defined as hyperkalemia, cough, hypotension, acute renal failure, malignancy, death).

ACE-inhibitor

Angiotensin-receptor blocker (ARB)

HMG-Coenzyme inhibitor (statin)

Spironolactone or Finerenone

Paricalcitol

SGLT2 inhibitor

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

kidney disease in Alport syndrome starts at birth, age at onset of end stage kidney failure in years

Alport syndrome starts at birth, age at death of patients in years

kidney disease in Alport syndrome starts at birth, eGFR-loss per year in ml/min/1.73m2

kidney disease in Alport syndrome starts at birth; time since birth to doubling (AS stages I or II) or tripling (AS stage 0) of UACR in years.

Prof. Dr. Oliver Gross

kidney disease in Alport syndrome starts at birth; change in albuminuria after birth

kidney disease in Alport syndrome starts at birth; change in proteinuria after birth

specific genetic variant: X-linked, digenic, autosomal heterozygous, homozygous, compound heterozygous

AEs of special interest: acute kidney renal failure, angioedema, hyperkalemia, dry cough, symptomatic hypotension (orthostatic collapse) and others, and death from all causes.

Alport syndrome is a genetic disease, hearing loss delevops over time since birth

Alport syndrome is a genetic disease, eye symptoms delevop over time since birth

age of relatives at start of renal replacement therapy in years

untreated patients, typically uncles or grandfathers of present patients. No Intervention (means no therapy until CKD stage V, on renal replacement therapy)

patients treated with medications with low eGFR (below 60 ml/min) (starts at patients with CKD stages III and IV).

therapy starts in patients with albuminuria >300mg/gCreatinine and eGFR higher than 60 ml/min.

therapy starts in patients with microhematuria only (usually at birth) or microalbuminuria (30-300 mg albumin per gCreatinine).

heterozygous patients with therapy (which also can be divided into subgroups stage T-0, I, II, III)

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

About this trial

Study ID

Status

Type

Placebo

Accepting

Trial Timing

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