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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Pediatric Kidney Disease; Alport Syndrome; Hereditary Kidney Disease; Thin Basement Membrane Disease; Familial Benign Hematuria
• Intervention / Treatment: Drug: ACE-inhibitor; Drug: AT1-inhibitor; Drug: HMG-Coenzyme inhibitor (statin); Drug: Spironolactone; Drug: Paricalcitol; Drug: SGLT2 inhibitor

Detailed 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.

• Study Type: Observational
• Enrollment (Anticipated): 500

Contacts and Locations

• Study Contact: Name: Oliver Gross, MD; Phone Number: 6331 +49-551-39-; Email: gross.oliver@med.uni-goettingen.de

Study Locations

• Germany
  • Goettingen, Germany, 37075
    • Recruiting
    • University Hospital Goettingen
    • Contact: Oliver Gross, MD; Phone Number: 8912 +49-551-39-; Email: gross.oliver@med.uni-goettingen.de

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Currently there are no causal therapeutic options which are proven to delay renal failure in AS. We established the European Alport Registry to collect data over several generations of Alport families across Europe. The 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).

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.

Description

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).

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Cross-Sectional

Number of groups / cohorts

6

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
no-T: untreated patients; 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; 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; observational study!; Other Names: Ramipril; Drug: AT1-inhibitor; observational study!; Drug: HMG-Coenzyme inhibitor (statin); observational study!; Drug: Spironolactone; observational study!; Drug: Paricalcitol; observational study!; Drug: SGLT2 inhibitor; observational study!
T-II: early therapy in patients; therapy starts at patients with proteinuria >0.3 g/day or per gCreatinine	Drug: ACE-inhibitor; observational study!; Other Names: Ramipril; Drug: AT1-inhibitor; observational study!; Drug: HMG-Coenzyme inhibitor (statin); observational study!; Drug: Spironolactone; observational study!; Drug: Paricalcitol; observational study!; Drug: SGLT2 inhibitor; observational study!
T-I: very early tharpy in patients; 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; observational study!; Other Names: Ramipril; Drug: AT1-inhibitor; observational study!; Drug: HMG-Coenzyme inhibitor (statin); observational study!; Drug: Spironolactone; observational study!; Drug: Paricalcitol; observational study!
no therapy in heterozygous carriers; heterozygous carriers without therapy
therapy in heterozygous carriers; heterozygous carriers with RAAS-blockade	Drug: ACE-inhibitor; observational study!; Other Names: Ramipril; Drug: AT1-inhibitor; observational study!; Drug: HMG-Coenzyme inhibitor (statin); observational study!; Drug: Spironolactone; observational study!; Drug: SGLT2 inhibitor; observational study!

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University Hospital Goettingen
• Collaborators: Society for Pediatric Nephrology (Germany); Deutsche Gesellschaft für Nephrologie; Alport Selbsthilfe e.V.; Association pour l'Information et la Recherche sur les Maladies Rénales Génétiques (AIRG); KfH Foundation Preventive Medicine
• Investigators: Principal Investigator: Oliver Gross, MD, University Hospital Goettingen

Publications and helpful links

General Publications

• Kashtan CE, Gross O. Clinical practice recommendations for the diagnosis and management of Alport syndrome in children, adolescents, and young adults-an update for 2020. Pediatr Nephrol. 2021 Mar;36(3):711-719. doi: 10.1007/s00467-020-04819-6. Epub 2020 Nov 6. Erratum In: Pediatr Nephrol. 2021 Jan 12;:
• Weinstock BA, Feldman DL, Fornoni A, Gross O, Kashtan CE, Lagas S, Lennon R, Miner JH, Rheault MN, Simon JF; Workshop Participants. Clinical trial recommendations for potential Alport syndrome therapies. Kidney Int. 2020 Jun;97(6):1109-1116. doi: 10.1016/j.kint.2020.02.029. Epub 2020 Apr 6.
• Temme J, Kramer A, Jager KJ, Lange K, Peters F, Muller GA, Kramar R, Heaf JG, Finne P, Palsson R, Reisaeter AV, Hoitsma AJ, Metcalfe W, Postorino M, Zurriaga O, Santos JP, Ravani P, Jarraya F, Verrina E, Dekker FW, Gross O. Outcomes of male patients with Alport syndrome undergoing renal replacement therapy. Clin J Am Soc Nephrol. 2012 Dec;7(12):1969-76. doi: 10.2215/CJN.02190312. Epub 2012 Sep 20.
• Temme J, Peters F, Lange K, Pirson Y, Heidet L, Torra R, Grunfeld JP, Weber M, Licht C, Muller GA, Gross O. Incidence of renal failure and nephroprotection by RAAS inhibition in heterozygous carriers of X-chromosomal and autosomal recessive Alport mutations. Kidney Int. 2012 Apr;81(8):779-83. doi: 10.1038/ki.2011.452. Epub 2012 Jan 11.
• Gross O, Licht C, Anders HJ, Hoppe B, Beck B, Tonshoff B, Hocker B, Wygoda S, Ehrich JH, Pape L, Konrad M, Rascher W, Dotsch J, Muller-Wiefel DE, Hoyer P; Study Group Members of the Gesellschaft fur Padiatrische Nephrologie, Knebelmann B, Pirson Y, Grunfeld JP, Niaudet P, Cochat P, Heidet L, Lebbah S, Torra R, Friede T, Lange K, Muller GA, Weber M. Early angiotensin-converting enzyme inhibition in Alport syndrome delays renal failure and improves life expectancy. Kidney Int. 2012 Mar;81(5):494-501. doi: 10.1038/ki.2011.407. Epub 2011 Dec 14.
• Stock J, Kuenanz J, Glonke N, Sonntag J, Frese J, Tonshoff B, Hocker B, Hoppe B, Feldkotter M, Pape L, Lerch C, Wygoda S, Weber M, Muller GA, Gross O. Prospective study on the potential of RAAS blockade to halt renal disease in Alport syndrome patients with heterozygous mutations. Pediatr Nephrol. 2017 Jan;32(1):131-137. doi: 10.1007/s00467-016-3452-z. Epub 2016 Jul 11.
• Frese J, Kettwig M, Zappel H, Hofer J, Grone HJ, Nagel M, Sunder-Plassmann G, Kain R, Neuweiler J, Gross O. Kidney Injury by Variants in the COL4A5 Gene Aggravated by Polymorphisms in Slit Diaphragm Genes Causes Focal Segmental Glomerulosclerosis. Int J Mol Sci. 2019 Jan 26;20(3):519. doi: 10.3390/ijms20030519.
• Boeckhaus J, Hoefele J, Riedhammer KM, Nagel M, Beck BB, Choi M, Gollasch M, Bergmann C, Sonntag JE, Troesch V, Stock J, Gross O. Lifelong effect of therapy in young patients with the COL4A5 Alport missense variant p.(Gly624Asp): a prospective cohort study. Nephrol Dial Transplant. 2022 Nov 23;37(12):2496-2504. doi: 10.1093/ndt/gfac006.
• Zhang Y, Bockhaus J, Wang F, Wang S, Rubel D, Gross O, Ding J. Genotype-phenotype correlations and nephroprotective effects of RAAS inhibition in patients with autosomal recessive Alport syndrome. Pediatr Nephrol. 2021 Sep;36(9):2719-2730. doi: 10.1007/s00467-021-05040-9. Epub 2021 Mar 27.

Study record dates

Study Major Dates

• Study Start: July 1, 1995
• Primary Completion (Actual): July 1, 2010
• Study Completion (Anticipated): January 1, 2035

Study Registration Dates

• First Submitted: February 26, 2015
• First Submitted That Met QC Criteria: February 26, 2015
• First Posted (Estimate): March 4, 2015

Study Record Updates

• Last Update Posted (Actual): May 24, 2022
• Last Update Submitted That Met QC Criteria: May 17, 2022
• Last Verified: May 1, 2022

More Information

Terms related to this study

• Keywords: Alport syndrome; thin basement membrane disease; familial benign hematuria
• Additional Relevant MeSH Terms: Pathologic Processes; Urologic Diseases; Disease; Urogenital Abnormalities; Congenital Abnormalities; Hemorrhage; Connective Tissue Diseases; Urination Disorders; Nephritis; Collagen Diseases; Syndrome; Kidney Diseases; Renal Insufficiency; Hematuria; Nephritis, Hereditary; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Enzyme Inhibitors; Hormones, Hormone Substitutes, and Hormone Antagonists; Protease Inhibitors; Natriuretic Agents; Diuretics; Hormone Antagonists; Mineralocorticoid Receptor Antagonists; Diuretics, Potassium Sparing; Spironolactone; Sodium-Glucose Transporter 2 Inhibitors; Ramipril; Angiotensin-Converting Enzyme Inhibitors
• Other Study ID Numbers: Alport-UMG2010