Findings from a recent study suggest that globotriaosylceramide (Gb3) and deacylated Gb3 (lyco-Gb3) lead to renal fibrosis in Fabry disease through different biochemical modulations. YJ Shin, MD, and colleagues reported study results online in Molecular Medicine Reports [doi:10.3892/mmr.2015.4010. Epub ahead of print].
Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the gene encoding the a-galactosidase A (a-Gal A) lysosomal enzyme, resulting in storage of Gb3 in vascular endothelial cells and different cell types throughout the body. When the kidney and heart are involved, it is life threatening; fibrosis of these organs is thought to be involved in the pathogenesis of Fabry disease.
It has also been suggested that an increased concentration of lyso-Gb3 in the plasma of symptomatic patients is a causative molecular event. To assess the molecular mechanisms involved in renal disease in Fabry disease, the researchers conducted an analysis of the changes in global gene expression before and after Gb3 or lyso-Gb3 treatment in two types of kidney cell lines: human proximal renal tubular epithelial (HK-2) and mouse renal glomerular mesangial (SV40 MES 13) cells.
In each cell type, Gb3 and lyso-Gb3 treatment regulated the expression of 199 and 328 genes, demonstrating a >2.0-fold change. The majority of the biologic functions of the regulated genes were associated with fibrogenesis or epithelial-mesenchymal transition (EMT). The gene expression patterns of sphingolipid-treated HK-2 cells were distinguishable from the patterns in the SV40 MES 13 cells.
The researchers selected several genes associated with the EMT and further evaluated in kidney cells and in Fabry mouse kidney tissues. In the SV40 MES 13 cells, the DLL1, F8, and HOXA11 genes were downregulated and FOXP2 was upregulated by treatment with Gb3 or lyso-Gb3. In the Hk-2 cells, the ADAMTS6, BEST1, IL4, and MYH11 genes were upregulated. In the mouse tissues, upregulation of the FOXP2, COL15A1, IL4, and MYH11 genes was also observed.
The gene expression profiles in kidney cells following the addition of Gb3 or lyso-Gb3 revealed substrate-specific and cell-specific patterns, suggesting that “Gb3 and lyso-Gb3 lead to renal fibrosis in Fabry disease through different biochemical modulations,” the researchers concluded.
Renal Transplantation in Patients with Fabry Disease
Conditions such as Anderson-Fabry disease include both structural and functional disorders; among these are diseases resulting from inborn errors of metabolism. In an article [in Italian] that appeared in G Ital Nefol [2015 Mar-Apr;32(2).pii:gin/32.2.30]. I Capelli and colleagues reported on “Kidney Transplantation and Inborn Errors of Metabolism.”
The fifth most common cause of end-stage renal disease is inherited kidney disease. Inherited kidney diseases are manifested in at least 150 different disorders, according to the researchers, with a prevalence of approximately 6080 cases per 100,000 in the United States and Europe. At least 10% of adults and nearly all children who progress to renal-replacement therapy have an inherited kidney disease.
Some inborn errors of metabolism primarily affect the kidney. Due to advances in effective renal-replacement therapies, patients with inherited kidney disorders rarely die when their disease progresses. Their quality of life, however, may be reduced due to compromised overall health.
In instances of patients with inborn errors of metabolism characterized by primary renal damage associated with dysfunction of a mutated protein, renal transplantation offers a viable treatment option. In such cases, the indication for renal transplantation makes it possible to overcome the specific enzyme defect.
The option remains valid even in cases where the genetic defect is expressed systemically and renal involvement is one of the clinical manifestations of the disease, such as in the case of Anderson-Fabry disease, the researchers said. In Anderson-Fabry disease, renal transplantation is combined with a liver (primary hyperoxaluria) or cardiac transplant (familial amyloidosis) to improve the patient’s quality of life as well as life expectancy.
Screening for Fabry Disease in Patients with CKD
Patients with chronic kidney disease can be screened for Fabry disease by measuring urinary globotriaosylceramide (Gb3, CD77) content. Fabry disease is a disorder caused by hampered Gb3 degradation. However, according to researchers, little is known about the factors other than Fabry disease that may influence urinary Gb3 excretion.
Martina Gaggl, MD, and colleagues recently conducted a study designed to identify routine diagnostic parameters as predictors of urinary Gb3 excretion in patients with CKD. They reported study results in the Journal of Nephrology [2015 Apr 10. Epub ahead of print].
The study included 609 participants with CKD stage 1-5. The researchers examined the influence of age, sex, renal function, urinary cell content, and chemical characteristics on urinary Gb3 concentrations (total Gb3, Gb3-24 isoform, and Gb3-24:18 isoform ratio). Measurements were determined by direct electorspray ionization mass spectrometry.
Among the 609 participants, median total urinary Gb3 was 233 ng.mg and the Gb3-24:18 isoform ratio was 1:2. Twenty-one patients without Fabry disease had a Gb3-24:18 isoform ratio ≥2.3. Excretion of total amount of Gb3 was higher in women, but the Gb3-24:18 isoform ratio in women was comparable to that in men. There was no influence of renal function or age on total Gb3, Gb3 isoforms, or the ratio. Only a distinct load of bacteria and leukocytes was associated with an increased Gb3 excretion. The Gb3-24:18 isoform ratio was not affected by urinary leukocytes, erythrocytes, bacteria, or protein content.
“The Gb3-24:18 isoform ratio is unaffected by several potential influencing variables and may thus be applied for screening for Fabry disease in unselected cohorts of patients presenting with CKD,” the researchers said.
Foot Process Effacement as Early Marker of Renal Disease
Globotriaosylceramid (Gb3) starts to accumulate in kidney cells in utero in individual with Fabry disease. Gb3 continues to accumulate during childhood and adulthood resulting in progression tissue damage, which may lead to renal failure. Camilla Tøndel, MD, PhD, and colleagues conducted an analysis of children with classic Fabry disease to examine whether foot process effacement can serve as an early marker of nephropathy in Fabry disease patients without albuminuria. They reported results in Nephron [2015;129(1):16-21].
The analysis included eight children with classic Fabry disease. Median age was 12 years (range, 4-16 years). All eight children had a renal biopsy performed prior to the initiation of enzyme replacement therapy (ERT). The children were all normalbuminuric and had normal glomerular filtration rate. Of the eight patients, three were re-biopsied after 3 or 5 years.
Significant Gb3 accumulation was found in several type of kidney cells with high amounts of Gb3 in the podocytes in all patients. In all but two patients, segmental podocyte foot process effacement was shown; there was no effacement in the youngest male patient (4 years of age) or in a male patient 12 years of age.
In a female patient 12 years of age, there was normal podocyte foot process prior to the start of ERT, but de novo foot process flattening and unchanged high score of podocyte Gb3 accumulation was found in the re-biopsy after 3 years of ERT (agalsidase alpha 0.2 mg.kg every other week). Worsening of podocyte effacement in kidney biopsy was seen in kidney biopsy after 5 years of agalsidase alpha 0.2 mg.kg every other week in two boys.
“Podocyte foot process effacement was found in the majority of eight young classical Fabry patients of both genders after the age of 11 years, without clinical signs of Fabry nephropathy. Kidney biopsies are essential in the early diagnosis of nephropathy and in the evaluation of the response to enzyme replacement therapy in early Fabry nephrology,” the researchers said.