Bedside Stereomicroscopy of Fabry Kidney Biopsies: An Easily Available Method for Diagnosis and Assessment of Sphingolipid Deposits

Abstract

Background/Aims: A previous case report found stereomicroscopic changes typical for Fabry disease in a kidney biopsy. This case series evaluates an expanded diagnostic capacity of the method. Methods: Bedside stereomicroscopy was performed in a cross-sectional prospective study of 31 consecutive enzyme-treated or treatment-naïve male (n = 14) and female Fabry disease patients. The burden of glomerular storage material was scored semiquantitatively on a visual analog scale (range 0-3) and a blinded comparison was done with a reference histologic method. Results: Significant correlations (p < 0.001) were found between the stereomicroscopic scoring of glomerular characteristic white storage material and the amount of podocyte globotriaosylceramide (Gb3) deposits scored by standardized light microscopy. The bedside method correctly identified the variability of podocyte Gb3 accumulation after 10 years of identical agalsidase therapy in 2 brothers aged 24 and 27 years, and also identified tubular cell deposits. Stereomicroscopy correctly verified the absence of sphingolipid deposits in the biopsy of a female index patient with a genetic variant of unknown significance, and the diagnosis of Fabry disease was finally discarded. Conclusions: Bedside stereomicroscopy of kidney biopsies is an easily available, low-cost microscopy method handled by the clinician. The method carries a high diagnostic sensitivity for Fabry disease, reducing the risk of misdiagnosis in previously unknown cases. An expanded yield of the method is suggested, including the grading of the podocyte Gb3 burden and assessment of effectiveness of enzyme replacement therapy. We recommend the method as complementary to current standard histologic evaluation of Fabry kidney biopsies.

Reduced α-galactosidase A activity in zebrafish (Danio rerio) mirrors distinct features of Fabry nephropathy phenotype

“…Taken together, these results are consistent with the general assumption that damage of the kidney filtration barrier results in protein leakage and elevated plasma creatinine which are critical in defining glomerular filtration rate loss [74] , [75] . Most importantly, similarities with human FD phenotype not associated with Gb3 accumulation support the important role of substrate independent pathophysiologic mechanisms in Fabry nephropathy [76] .…”

Enzyme Replacement Therapy Clears Gb3 Deposits from a Podocyte Cell Culture Model of Fabry Disease but Fails to Restore Altered Cellular Signaling

“…Since our data points to additional, yet unknown disease mechanisms and a point of no return despite Gb3 clearance, these findings may underscore that early treatment initiation is crucial in Fabry disease patients to prevent irreversible cellular damage [30]. New diagnostic strategies employing the advances in mass spectrometry [31][32][33] as well as initiating kidney biopsies in Fabry disease patients earlier in the course of the disease have already been suggested [34][35][36][37].…”

Biomarkers of Fabry Nephropathy: Review and Future Perspective

“…The score quantifies the Gb3 density deposition in glomeruli, interstitium, and vessels, as well as progressive lesions (glomerulosclerosis, ischemic glomeruli, and tubulointerstitial fibrosis). Recently, bedside stereomicroscopy for Fabry kidney biopsies has been recommended as a complementary method to current histologic evaluation as it was demonstrated to have high diagnostic sensitivity for FD [55].…”