Mosaicism of Podocyte Involvement Is Related to Podocyte Injury in Females with Fabry Disease

Abstract

BackgroundFabry disease. an X-linked deficiency of α-galactosidase A coded by the GLA gene, leads to intracellular globotriaosylceramide (GL-3) accumulation. Although less common than in males, chronic kidney disease, occurs in ∼15% of females. Recent studies highlight the importance of podocyte injury in Fabry nephropathy development and progression. We hypothesized that the greater the % of podocytes with active wild-type GLA gene (due to X-inactivation of the mutant copy) the less is the overall podocyte injury.MethodsKidney biopsies from 12 treatment-naive females with Fabry disease, ages 15 (8–63), median [range], years were studied by electron microscopy and compared with 4 treatment-naive male patients.ResultsIn females, 51 (13–100)% of podocytes (PC) per glomerulus had no GL-3 inclusions, this consistent with a non-Fabry podocyte phenotype (NFPC). In PC with GL-3 inclusions [Fabry podocyte phenotype (FPC)], GL-3 volume density per podocyte was virtually identical in females and males, consistent with little or no cross-correction between FPC and NFPC. %NFPC per glomerulus (%NFPC/glom) correlated with age in females (r = 0.65, p = 0.02), suggesting a survival disadvantage for FPC over time. Age-adjusted %NFPC/glom was inversely related to foot process width (FPW) (r = −0.75, p = 0.007), an indicator of PC injury. GL-3 volume density in FPC in females correlated directly with FPW.ConclusionsThese findings support important relationships between podocyte mosaicism and podocyte injury in female Fabry patients. Kidney biopsy, by providing information about podocyte mosaicism, may help to stratify females with Fabry disease for kidney disease risk and to guide treatment decisions.

Characterization of Classical and Nonclassical Fabry Disease: A Multicenter Study

“…This is assumed to be caused by disease modifiers or in the case of women, skewed X inactivation. [7][8][9] As an alternative, plasma ly-soGb3 concentrations are a valuable tool in the classification of FD. 4,24 In line with earlier findings, 4 lysoGb3 concentrations can, indeed, be used to differentiate between phenotypes in men with FD.…”

“…6 It is hypothesized that skewed X inactivation underlies the variability of the phenotype in women. [7][8][9] Treatment of FD consists of enzyme replacement therapy (ERT) and adjunctive treatment, including ACE inhibitors or angiotensin receptor blockers, antiplatelet drugs, and analgesics. Studies have shown that ERT can delay but not always prevent some of the clinical complications of the disease.…”

Urinary Podocyte Loss Is Increased in Patients with Fabry Disease and Correlates with Clinical Severity of Fabry Nephropathy

“…This need is even greater in female patients, where heterogeneity in phenotype severity is even greater, perhaps in part, related to mosaicism of podocyte involvement. [27] In another study, Trimarchi et al . found increased podocyturia in Fabry patients, but with no correlation between urine podocyte density and either proteinuria or eGFR.…”

A Novel Missense GLA Mutation (p.G35V) Detected in Hemodialysis Screening Leads to Severe Systemic Manifestations of Fabry Disease in Men and Women

“…Mosaicism of kidney involvement, probably due to the random X-inactivation, may play a pivotal role on the heterogeneous histologic findings of Fabry nephropathy in female patients [37]. The variable agreement between the podocyte vacuolization score, observed by light microscopy, and that of podocyte inclusion, observed by semi-thin slicing, reinforces the importance of both methods for evaluating podocyte deposits.…”