Natural History and Structural Functional Relationships in Fabry Renal Disease Treatment Outcomes(Changes)in Fabry Renal Disease Study
| Status: | Recruiting |
|---|---|
| Conditions: | Renal Impairment / Chronic Kidney Disease, Hematology, Metabolic |
| Therapuetic Areas: | Hematology, Nephrology / Urology, Pharmacology / Toxicology |
| Healthy: | No |
| Age Range: | 1 - 75 |
| Updated: | 5/4/2018 |
| Start Date: | October 2010 |
| End Date: | September 2020 |
| Contact: | Michael Mauer, MD |
| Email: | mauer002@umn.edu |
| Phone: | 612-626-2720 |
Natural History and Structural Functional Relationships in Fabry Renal Disease Natural History, Structural Functional Relationships and Determinants of Renal Structural Responses (Changes) With Enzyme Replacement Therapy in Fabry Disease
The investigators will perform a study with two major components. The first is a natural
history study of untreated Fabry patients. This study component will detail kidney
microscopic structural changes in Fabry patients before starting enzyme replacement therapy
and will correlate these changes with kidney function, including glomerular filtration rate
and urinary albumin excretion rate. The investigators will perform studies on samples
obtained at baseline, or before enzyme replacement therapy is initiated. The goal of our
study is to find kidney microscopic changes in the biopsies that are associated with kidney
disfunction. Our hypotheses for this study are:
1. Much of the natural history of Fabry renal structural changes will occur without
detectable renal functional alterations.
2. Structural changes associated with the initial onset of proteinuria and those associated
with the subsequent progressive loss of filtration function will differ and will be best
described by non-linear models.
3. There will be sufficient precision of Fabry renal structural-functional relationships to
support renal structure as an acceptable clinical trial surrogate endpoint for later
renal functional deterioration.
The second component examines the effects of age and gender at start of enzyme replacement
therapy (ERT), as well as dosage levels of ERT on the renal cellular clearance of GL3 from
Fabry patients by comparing baseline to follow-up kidney biopsies performed 5, 11, and 60
months later, with all comparisons matched for ERT treatment duration. Our hypotheses for
this component of the study are as follows:
1. Enzyme Replacement Therapy(ERT) instituted at younger ages is more effective in reducing
podocytes(PC),distal tubular cells(DTC),and arterial smooth muscle cells (ASMC)GL-3 than
in older Fabry patients.
2. Earlier institution of ERT will stabilize PC numbers while later ERT institution,
especially in proteinuric adults, may not prevent progressive decline in PC numbers and
associated glomerular sclerosis, tubulointerstitial injury, and GFR loss.
3. Whereas lower ERT dose may effectively clear GL-3 from endothelial and mesangial cells,
it will be less effective in clearing GL-3 from PC and also from DTC and ASMC.
4. Affected cells will be cleared of GL-3 equivalently in females and males.
history study of untreated Fabry patients. This study component will detail kidney
microscopic structural changes in Fabry patients before starting enzyme replacement therapy
and will correlate these changes with kidney function, including glomerular filtration rate
and urinary albumin excretion rate. The investigators will perform studies on samples
obtained at baseline, or before enzyme replacement therapy is initiated. The goal of our
study is to find kidney microscopic changes in the biopsies that are associated with kidney
disfunction. Our hypotheses for this study are:
1. Much of the natural history of Fabry renal structural changes will occur without
detectable renal functional alterations.
2. Structural changes associated with the initial onset of proteinuria and those associated
with the subsequent progressive loss of filtration function will differ and will be best
described by non-linear models.
3. There will be sufficient precision of Fabry renal structural-functional relationships to
support renal structure as an acceptable clinical trial surrogate endpoint for later
renal functional deterioration.
The second component examines the effects of age and gender at start of enzyme replacement
therapy (ERT), as well as dosage levels of ERT on the renal cellular clearance of GL3 from
Fabry patients by comparing baseline to follow-up kidney biopsies performed 5, 11, and 60
months later, with all comparisons matched for ERT treatment duration. Our hypotheses for
this component of the study are as follows:
1. Enzyme Replacement Therapy(ERT) instituted at younger ages is more effective in reducing
podocytes(PC),distal tubular cells(DTC),and arterial smooth muscle cells (ASMC)GL-3 than
in older Fabry patients.
2. Earlier institution of ERT will stabilize PC numbers while later ERT institution,
especially in proteinuric adults, may not prevent progressive decline in PC numbers and
associated glomerular sclerosis, tubulointerstitial injury, and GFR loss.
3. Whereas lower ERT dose may effectively clear GL-3 from endothelial and mesangial cells,
it will be less effective in clearing GL-3 from PC and also from DTC and ASMC.
4. Affected cells will be cleared of GL-3 equivalently in females and males.
Fabry disease is a rare genetic disease with deficient activity of enzyme alpha-galactosidase
A. Deficient activity of this enzyme leads to the accumulation of lipid-derived inclusions in
different organs including kidney, heart and vessels. These inclusions can be found in the
kidney even before birth. The earliest known clinical manifestation of Fabry kidney disease
is the appearance of excess protein in the urine, which usually occurs in the second decade
of life. However, our studies, as well as those of other investigators show evidence that
kidney injury starts much earlier. Once excess protein is found in the urine, kidney function
deterioration becomes progressive, and most Fabry patients require kidney transplantation or
hemodialysis in the third to fifth decade of life. The lesion or composite of lesions
responsible for functional deterioration of the kidney in Fabry disease are not well known.
Their delineation using quantitative, unbiased, morphometric methods will help to understand
this disease, and to develop surrogate structural outcomes for early intervention trials.
Enzyme replacement therapy may stabilize kidney function. However, its long-term effect on
kidney survival is not known. Moreover, there is no early known predictor of kidney
dysfunction to adjust and evaluate effectiveness of enzyme replacement therapy. Our studies
of renal GL-3 clearance comparing pre-and post-ERT renal biopsies using the above methods
will allow us to determine whether age at institution of treatment and ERT dose affect ERT
induced GL-3 cellular clearance, especially from those cells where ERT is less effective,
i.e., podocytes, vascular smooth muscle cells and distal tubular cells. Finally, it is our
hypothesis that mosaicism in Fabry disease females is such that cells such as podocytes are
either affected or normal and that ERT clearance in the affected podocytes in females will,
as in males, be dependant on age of institution of treatment and ERT dose.
A. Deficient activity of this enzyme leads to the accumulation of lipid-derived inclusions in
different organs including kidney, heart and vessels. These inclusions can be found in the
kidney even before birth. The earliest known clinical manifestation of Fabry kidney disease
is the appearance of excess protein in the urine, which usually occurs in the second decade
of life. However, our studies, as well as those of other investigators show evidence that
kidney injury starts much earlier. Once excess protein is found in the urine, kidney function
deterioration becomes progressive, and most Fabry patients require kidney transplantation or
hemodialysis in the third to fifth decade of life. The lesion or composite of lesions
responsible for functional deterioration of the kidney in Fabry disease are not well known.
Their delineation using quantitative, unbiased, morphometric methods will help to understand
this disease, and to develop surrogate structural outcomes for early intervention trials.
Enzyme replacement therapy may stabilize kidney function. However, its long-term effect on
kidney survival is not known. Moreover, there is no early known predictor of kidney
dysfunction to adjust and evaluate effectiveness of enzyme replacement therapy. Our studies
of renal GL-3 clearance comparing pre-and post-ERT renal biopsies using the above methods
will allow us to determine whether age at institution of treatment and ERT dose affect ERT
induced GL-3 cellular clearance, especially from those cells where ERT is less effective,
i.e., podocytes, vascular smooth muscle cells and distal tubular cells. Finally, it is our
hypothesis that mosaicism in Fabry disease females is such that cells such as podocytes are
either affected or normal and that ERT clearance in the affected podocytes in females will,
as in males, be dependant on age of institution of treatment and ERT dose.
Inclusion Criteria:
- Patients diagnosed with Fabry disease who have/have not received enzyme replacement
therapy where a clinical decision has been made to obtain a kidney biopsy, a GFR, and
urinary albumin studies or where patients have previously completed clinical trials
which included measures of renal function and renal biopsies.
Exclusion Criteria:
- Patients with serum creatinine more than 2.5 mg/dL or known to have a renal disease
other than Fabry.
We found this trial at
2
sites
Minneapolis, Minnesota 55455
Phone: 612-626-2720
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