Clinical trial NCT02994303: Podocyturia - Predictor of Renal Dysfunction in Fabry Nephropathy
Official title: Podocyturia, a Non-Invasive Predictor of Renal Dysfunction in Fabry Nephropathy
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Fabry Disease
Keywords: Fabry disease
Fabry nephropathy
end-stage renal disease
Anderson-Fabry disease
Fabry's disease
Lead sponsor: University of Washington
Sponsor class: OTHER
Collaborators: name: Rare Diseases Clinical Research Network
name: National Center for Advancing Translational Sciences (NCATS)
name: National Institute of Neurological Disorders and Stroke (NINDS)
name: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
name: Lysosomal Disease Network
First posted: 2016-12-15
Enrollment: 58
Sex: ALL
Minimum age (years): 1
Maximum age (years): 90
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: CASE_ONLY
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Patients of any gender who have been diagnosed with Fabry disease

Brief summary: In patients with Fabry disease, this research study explores the presence of podocytes in their urine as a potential non-invasive biomarker for baseline kidney disease; and explores changes in the quantity of podocytes in their urine over time as a predictor for kidney disease progression. To accomplish this, the investigators will evaluate the quantification of podocytes in the urine of Fabry disease patients at baseline and longitudinally over time. This study requires a single patient visit, during which the patient provides a urine specimen. The research team will then collect the patient's kidney function data proximate to the time of urine collection, and follow the patient's kidney function data longitudinally over the five years of this study by reviewing their medical charts. The study offers no interventions.

Detailed description: Despite long-term recombinant enzyme replacement therapy, kidney failure remains a common and important complication of Fabry disease. Recent studies suggest that early administration of enzyme replacement therapy in sufficient dosage may prevent progression of kidney failure in patients with Fabry disease. Currently, there is no reliable non-invasive biomarker to detect early, occult kidney injury in these patients. Such early kidney injury detection is critical for guiding the decision as to when to initiate enzyme replacement therapy, and for identifying those patients with more severe kidney injury who may need higher doses of enzyme replacement therapy or additional forms of therapy.

Podocytes are special kidney cells with a crucial role in preventing escape of protein from the blood into the urine. Biopsy studies of Fabry disease patients suggest that podocyte injury occurs early and is progressive with increasing age in young Fabry disease patients. It is also likely that podocyte injury and loss leads to irreversible kidney lesions in later stages of Fabry disease nephropathy. Because injured podocytes are sloughed off into the urine (a manifestation known as podocyturia), quantification of urine podocytes might serve as a non-invasive and sensitive biomarker useful for predicting Fabry disease nephropathy risk; and to guide more effective Fabry disease treatment.

The investigators' preliminary data show correlations between presence of urinary podocytes and other markers of renal disease in adult Fabry disease patients; however, these cross-sectional data need to be expanded. The investigators have no information as to whether this potential biomarker could predict progression of the disease.

The investigators hypothesize that since podocyte injury plays a central role in kidney complications of Fabry disease, podocyte loss detected in the urine will identify patients with greater underlying kidney disease, and will identify patients with greater propensity for kidney disease progression. They also hypothesize that the number of podocytes in the urine of patients with Fabry disease will correlate directly with these patients' proteinuria, and will correlate inversely with their glomerular filtration rate (GFR) at baseline. Additionally the investigators hypothesize that the number of podocytes in the urine of patients with Fabry disease will predict increase in proteinuria and decline in glomerular filtration rate, as measured during long-term patient follow-up.

Data to be collected include identification of these patients' GLA gene mutation; measurement of their baseline a-galactosidase A enzyme activity; their baseline age, gender, height and weight; measurement of their baseline serum creatinine (SCr), eGFR, PCR and ACR; these patients' family history of Fabry disease, their history of kidney or systemic diseases, their medications including enzyme replacement therapy, and their medical information about other complications of Fabry disease (such as cardiomyopathy, arrhythmias, neuropathy and gastrointestinal problems).

Eligibility criteria: Inclusion Criteria:

* Patients must have been diagnosed with Fabry disease
* Patients must be between the ages of 1 day-90 years

Exclusion Criteria:

* Fabry disease patients who have had a renal transplant
* Fabry disease patients who are, or have been, subjects in any investigational drug study

Primary outcomes:
measure: Detection of Podocyturia in Subjects Diagnosed with Fabry Disease
timeFrame: At time of enrollment
Secondary outcomes:
measure: Change from Baseline in Number of Urine Podocytes at Year 1, 2, 3, 4 and 5
timeFrame: Annually at Year 1, Year 2, Year 3, Year 4 and Year 5
measure: Change from Baseline in urine protein/creatinine ratio (PCR) at Year 1, 2, 3, 4 and 5
timeFrame: At time of enrollment, then annually at Year 1, Year 2, Year 3, Year 4 and Year 5
measure: Change from Baseline in urine albumin/creatinine ratio (ACR) at Year 1, 2, 3, 4 and 5
timeFrame: At time of enrollment, then annually at Year 1, Year 2, Year 3, Year 4 and Year 5
measure: Change from Baseline in estimated glomerular filtration rate (eGFR) at Year 1, 2, 3, 4 and 5
timeFrame: At time of enrollment, then annually at Year 1, Year 2, Year 3, Year 4 and Year 5
measure: Change from Baseline in Number of Urine Podocytes at Year 1, 2, 3, 4 or 5, Based On Subject's New Urine Sample
timeFrame: Annually at Year 1, Year 2, Year 3, Year 4 or Year 5
Other outcomes:
Locations:
city: Decatur
country: United States
facility: Emory University
state: Georgia
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: Seattle
country: United States
facility: University of Washington
state: Washington
Study officials:
affiliation: University of Washington Associate Professor, Pathology
name: Behzad Najafian, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Najafian B, Tondel C, Svarstad E, Sokolovkiy A, Smith K, Mauer M. One Year of Enzyme Replacement Therapy Reduces Globotriaosylceramide Inclusions in Podocytes in Male Adult Patients with Fabry Disease. PLoS One. 2016 Apr 15;11(4):e0152812. doi: 10.1371/journal.pone.0152812. eCollection 2016.
citation: Najafian B, Fogo AB, Lusco MA, Alpers CE. AJKD Atlas of Renal Pathology: Fabry nephropathy. Am J Kidney Dis. 2015 Nov;66(5):e35-6. doi: 10.1053/j.ajkd.2015.08.006. No abstract available.
citation: Wijburg FA, Benichou B, Bichet DG, Clarke LA, Dostalova G, Fainboim A, Fellgiebel A, Forcelini C, An Haack K, Hopkin RJ, Mauer M, Najafian B, Scott CR, Shankar SP, Thurberg BL, Tondel C, Tylki-Szymanska A, Ramaswami U. Characterization of early disease status in treatment-naive male paediatric patients with Fabry disease enrolled in a randomized clinical trial. PLoS One. 2015 May 8;10(5):e0124987. doi: 10.1371/journal.pone.0124987. eCollection 2015.
citation: Mauer M, Glynn E, Svarstad E, Tondel C, Gubler MC, West M, Sokolovskiy A, Whitley C, Najafian B. Mosaicism of podocyte involvement is related to podocyte injury in females with Fabry disease. PLoS One. 2014 Nov 11;9(11):e112188. doi: 10.1371/journal.pone.0112188. eCollection 2014.
citation: Najafian B, Mauer M, Hopkin RJ, Svarstad E. Renal complications of Fabry disease in children. Pediatr Nephrol. 2013 May;28(5):679-87. doi: 10.1007/s00467-012-2222-9. Epub 2012 Aug 17.
citation: Najafian B, Mauer M. Quantitating glomerular endothelial fenestration: an unbiased stereological approach. Am J Nephrol. 2011;33 Suppl 1(Suppl 1):34-9. doi: 10.1159/000327075. Epub 2011 Jun 10.
citation: Najafian B, Svarstad E, Bostad L, Gubler MC, Tondel C, Whitley C, Mauer M. Progressive podocyte injury and globotriaosylceramide (GL-3) accumulation in young patients with Fabry disease. Kidney Int. 2011 Mar;79(6):663-670. doi: 10.1038/ki.2010.484. Epub 2010 Dec 15.
citation: Ramaswami U, Najafian B, Schieppati A, Mauer M, Bichet DG. Assessment of renal pathology and dysfunction in children with Fabry disease. Clin J Am Soc Nephrol. 2010 Feb;5(2):365-70. doi: 10.2215/CJN.08091109. Epub 2010 Jan 7.
citation: Mauer M, Najafian B. Implications of early renal changes in Fabry disease. Clin Ther. 2008;30 Suppl B:S40. doi: 10.1016/s0149-2918(08)80034-3. No abstract available.
citation: Hopkin RJ, Cabrera G, Charrow J, Lemay R, Martins AM, Mauer M, Ortiz A, Patel MR, Sims K, Waldek S, Warnock DG, Wilcox WR. Risk factors for severe clinical events in male and female patients with Fabry disease treated with agalsidase beta enzyme replacement therapy: Data from the Fabry Registry. Mol Genet Metab. 2016 Sep;119(1-2):151-9. doi: 10.1016/j.ymgme.2016.06.007. Epub 2016 Jun 13.
citation: Hopkin RJ, Jefferies JL, Laney DA, Lawson VH, Mauer M, Taylor MR, Wilcox WR; Fabry Pediatric Expert Panel. The management and treatment of children with Fabry disease: A United States-based perspective. Mol Genet Metab. 2016 Feb;117(2):104-13. doi: 10.1016/j.ymgme.2015.10.007. Epub 2015 Oct 23.
citation: Warnock DG, Mauer M. Fabry disease: dose matters. J Am Soc Nephrol. 2014 Apr;25(4):653-5. doi: 10.1681/ASN.2013121322. Epub 2014 Feb 20. No abstract available.
citation: Fall B, Scott CR, Mauer M, Shankland S, Pippin J, Jefferson JA, Wallace E, Warnock D, Najafian B. Urinary Podocyte Loss Is Increased in Patients with Fabry Disease and Correlates with Clinical Severity of Fabry Nephropathy. PLoS One. 2016 Dec 16;11(12):e0168346. doi: 10.1371/journal.pone.0168346. eCollection 2016.