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.
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.
Patients with serum creatinine more than 2.5 mg/dL or known to have a renal disease other than Fabry.
50-60 male and female adults and children with Fabry disease who either have or have not been initiated on enzyme replacement therapy, and whose physicians have determined that a kidney biopsy and renal functional studies are clinically indicated before initiation of enzyme replacement therapy and as follow-up for this therapy or who have completed clinical trials of ERT, have baseline or baseline and and follow biopsies, and have consented to allow their tissues to be examined for research purposes. We are expecting to recruit patients from many different centers.
Cohort
Prospective
Not listed
Natural History and Determinants of Renal Structural Responses (Changes) to Enzyme Replacement Therapy in Fabry Disease
Renal function measurements for the cross sectional natural history component will be urine protein excretion and measured/estimated GFR. Renal biopsies will provide estimates of the amount of GL-3 in various kidney structures. We will determine which structural parameter or composite of structural parameters is most closely associated with kidney function. For renal structural responses (changes) with ERT the primary outcome will the magnitude of reduction in podocyte GL-3 per glomerulus after (a)5 months, (b) 11 months, and (c) 60 months of ERT.
Natural History and Determinants of Renal Structural Responses (Changes) to Enzyme Replacement Therapy in Fabry Disease
The secondary endpoint for the determinants of renal structural responses to ERT will be GL-3 reduction from baseline to 5, 11 and 60 months in a composite of structural parameters which will be determined in our natural history studies.
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University of Minnesota
Lead sponsor
Rare Diseases Clinical Research Network
Collaborator
National Center for Advancing Translational Sciences (NCATS)
Collaborator
National Institute of Neurological Disorders and Stroke (NINDS)
Collaborator
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Collaborator
Washington University School of Medicine
Collaborator
Haukeland University Hospital
Collaborator
