globotriaosylceramide and Proteinuria

Progressive nephropathy is one of the main features of Fabry disease. Although some clinical signs of Fabry nephropathy are already present in childhood, patients are often diagnosed relatively late in the course of the disease due to the absence of specific clinical markers, while a timely diagnosis and the prompt start of enzyme replacement therapy may be beneficial in stabilizing renal function or slowing its decline. Proteinuria/albuminuria has been accepted as the most important marker for Fabry nephropathy; however, a large proportion of renal impairment occurs in nonalbuminuric state. Therefore, early biomarkers may be useful for early identification of kidney involvement. The aim of this article is to review the current available literature on all biomarkers of Fabry nephropathy, with a comprehensive and critical description of their utilization in early recognition of renal damage.

Topics: Alpha-Globulins; Biomarkers; Cystatin C; Cysts; Early Diagnosis; Enzyme Replacement Therapy; Fabry Disease; Female; Glomerular Filtration Rate; Humans; Male; Proteinuria; Proteomics; Trihexosylceramides; Urine

While females can suffer serious complications of Fabry disease, most studies are limited to males to avoid confounding by mosaicism. Here, we developed a novel unbiased method for quantifying globotriaosylceramide (GL3) inclusion volume in affected podocytes (F+) in females with Fabry disease independent of mosaicism leading to important new observations. All podocytes in male patients with Fabry are F+. The probability of observing random profiles from F+ podocytes without GL3 inclusions (estimation error) was modeled from electron microscopic studies of 99 glomeruli from 40 treatment-naïve males and this model was applied to 28 treatment-naïve females. Also, podocyte structural parameters were compared in 16 age-matched treatment-naïve males and females with classic Fabry disease and 11 normal individuals. A 4

Topics: Fabry Disease; Female; Humans; Male; Podocytes; Proteinuria; Trihexosylceramides

Fabry disease (FD) is an X-linked inherited glycosphingolipid metabolism disorder, therefore, heterozygous female FD patients display highly variable clinical symptoms, disease severity, and pathological findings. This makes it very challenging to diagnosing female patients with FD. A 69-year-old Japanese female was introduced to the nephrologist for the evaluation of proteinuria. A renal biopsy was performed. Although the light microscopic examinations revealed that most of the glomeruli showed minor glomerular abnormalities, however, vacuolation was apparently found in the tubular epithelial cells. Immunofluorescence staining for globotriaosylceramide was positively detected in some podocytes and distal tubular epithelial cells. In addition, myelin-like structure (zebra body) was detected by electron microscopy. Pathological findings were most consistent with FD. Consequently, biochemical and genetic analysis confirmed the diagnosis of female FD. Enzyme replacement therapy was performed in conjunction with renin-angiotensin aldosterone system inhibitors and beta-blockers. The patient's family members received the analysis, and the same DNA missense mutation was detected in the patient's grandson. The enzyme replacement therapy was introduced to the grandson. The present case showed that renal biopsy can contribute towards a correct diagnosis for FD. Particularly, in female FD patients, careful examination of pathological changes is essential, for example, vacuolation of any type of renal cells may be a clue for the diagnosis.

Topics: Aged; Asian People; Biopsy; Enzyme Replacement Therapy; Fabry Disease; Female; Heterozygote; Humans; Kidney; Kidney Glomerulus; Microscopy, Electron; Mutation, Missense; Podocytes; Proteinuria; Severity of Illness Index; Trihexosylceramides

Topics: Adolescent; alpha-Galactosidase; Biopsy; Consanguinity; Fabry Disease; Female; Hearing Loss, Sensorineural; Humans; Kidney; Male; Mass Screening; Microscopy, Electron; Pedigree; Proteinuria; Sex Factors; Trihexosylceramides

Fabry disease is an X-linked glycosphingolipidosis caused by deficient synthesis of the enzyme α-galactosidase A, which results in accumulations of globotriaosylceramide (GL-3) in systemic tissues. Nephropathy is a dominant feature of Fabry disease. It still remains unclear how the nephropathy progresses. Recombinant agalsidase replacement therapy is currently the only approved, specific therapy for Fabry disease. The optimal dose of replacement enzyme also still remains unclear. The worldwide shortage of agalsidase-β in 2009 forced dose reduction of administration. It showed that the proteinuria emerged like surges, followed by temporary plasma GL-3 elevations in the early stages of classic Fabry disease. Additionally, it also showed that 1 mg/kg of agalsidase-β every other week could clear the GL-3 accumulations from podocytes and was required to maintain negative proteinuria and normal plasma GL-3 levels.. This observation of a young patient with classic Fabry disease about 5 years reveals that the long-term, low-dose agalsidase-β caused proteinuria surges, but not persistent proteinuria, followed by temporary plasma GL-3 elevations, and agalsidase-β at 1 mg/kg every other week could clear accumulated GL-3 from podocytes and was required to maintain normal urinalysis and plasma GL-3 levels.

Topics: Adolescent; alpha-Galactosidase; Enzyme Replacement Therapy; Fabry Disease; Humans; Isoenzymes; Kidney Diseases; Male; Podocytes; Proteinuria; Trihexosylceramides

The effect of early-onset enzyme replacement therapy on renal morphologic features in Fabry disease is largely unknown. Here, we evaluated the effect of 5 years of treatment with agalsidase alfa or agalsidase beta in 12 consecutive patients age 7-33 years (median age, 16.5 years). We performed renal biopsies at baseline and after 5 years of enzyme replacement therapy; 7 patients had additional biopsies after 1 and 3 years. After a median of 65 months, biopsy findings from all patients showed total clearance of glomerular endothelial and mesangial cell inclusions, and findings from 2 patients showed complete clearance of inclusions from epithelial cells of the distal tubule. The 4 patients who received the highest dose of agalsidase exhibited substantial clearance of podocyte inclusions, and the youngest patient had nearly complete clearance of these inclusions. Linear regression analysis showed a highly significant correlation between podocyte globotriaocylceramide clearance and cumulative agalsidase dose (r=0.804; P=0.002). Microalbuminuria normalized in five patients. In summary, long-term enzyme replacement therapy in young patients can result in complete globotriaocylceramide clearance of mesangial and glomerular endothelial cells across all dosage regimens, and clearance of podocyte inclusions is dose-dependent.

Topics: Adolescent; Adult; alpha-Galactosidase; Biopsy; Child; Enzyme Replacement Therapy; Fabry Disease; Female; Humans; Isoenzymes; Kidney; Kidney Function Tests; Male; Proteinuria; Recombinant Proteins; Trihexosylceramides; Young Adult

Progressive renal failure often complicates Fabry disease, the pathogenesis of which is not well understood. To further explore this we applied unbiased stereological quantitative methods to electron microscopic changes of Fabry nephropathy and the relationship between parameters of glomerular structure and renal function in 14 young Fabry patients (median age 12 years). Renal biopsies were obtained shortly before enzyme replacement therapy from these patients and from nine normal living kidney donors as controls. Podocyte globotriaosylceramide (GL-3) inclusion volume density increased progressively with age; however, there were no significant relationships between age and endothelial or mesangial inclusion volume densities. Foot process width, greater in male Fabry patients, also progressively increased with age compared with the controls, and correlated directly with proteinuria. In comparison to the biopsies of the controls, endothelial fenestration was reduced in Fabry patients. Thus, our study found relationships between quantitative parameters of glomerular structure in Fabry nephropathy and age, as well as urinary protein excretion. Hence, podocyte injury may play a pivotal role in the development and progression of Fabry nephropathy.

Topics: Adolescent; Age Factors; Biomarkers; Biopsy; Case-Control Studies; Child; Child, Preschool; Creatinine; Disease Progression; Endothelial Cells; Europe; Fabry Disease; Female; Glomerular Filtration Rate; Humans; Kidney Glomerulus; Least-Squares Analysis; Linear Models; Male; Podocytes; Proteinuria; Renal Insufficiency; Risk Assessment; Risk Factors; Sex Factors; Trihexosylceramides; United States; Up-Regulation; Young Adult

It is suggested that biomarkers of renal complications of Fabry disease are likely to be useful for diagnosis and to follow the natural disease progression or the effect of specific therapeutic interventions. Traditionally, globotriaosylceramide (Gb(3)) in urine has been used to evaluate the effect of specific therapy, such as enzyme replacement therapy (ERT). Although urinary Gb(3) decreases significantly with ERT, it has not yet been shown to be a valid surrogate marker in treatment trials. We propose a detailed study of the nature and origin of Gb(3) combined with a prospective collaborative trial that combines Gb(3) changes with the effect of ERT on clinical nephrological outcome measures. Existing biomarkers such as general proteinuria/albuminuria or specific proteins such as N-acetyl-beta-D-glucosaminidase should be evaluated along with novel proteomic or metabolomic studies for biomarker discovery using mass spectrometry or nuclear magnetic resonance. Standard scoring of all pathologic aspects of kidney biopsies may also be a promising way to assess the effect of therapy.

Topics: Biomarkers; Biopsy; Disease Progression; Enzyme Replacement Therapy; Fabry Disease; Humans; Kidney Diseases; Metabolomics; Predictive Value of Tests; Proteinuria; Proteomics; Treatment Outcome; Trihexosylceramides

Topics: Adult; Age of Onset; Child; Endpoint Determination; Fabry Disease; Humans; Kidney; Kidney Failure, Chronic; Proteinuria; Trihexosylceramides

The prognosis of Fabry disease has changed since enzyme-replacement treatment was introduced. Therefore, early diagnosis is instrumental. We describe a family presenting with chronic renal failure and proteinuria in which classic skin and neurological features were absent and the diagnosis of Fabry disease was difficult and not established until a second family member developed renal abnormalities. A 35-year-old man was admitted because he was overweight and had hypertension, with a serum creatinine level of 1.3 mg/dL (115 micromol/L) and protein excretion of 870 mg/d. Because 1 brother, who died years ago at the age of 32 years of acute myeloid leukemia, also had chronic renal failure and proteinuria, the diagnosis of Fabry disease was entertained. In the index patient, acroparesthesia, hypohidrosis, pain, angiokeratomas of the skin, and cornea verticillata suggesting Fabry disease were absent. Conversely, renal biopsy showed typical globotriaosylceramide deposits, and leukocyte alpha-galactosidase (alpha-GLA) A activity was decreased. Analysis of the alpha-GLA gene showed the mutation E66K. The mutation also was found in another asymptomatic 30-year-old brother who also had chronic renal failure and proteinuria, but normal extrarenal findings. In the brother who died, Fabry disease, missed at autopsy because of cancer-related findings, could be confirmed after repeated review of histological slides. Mutation carriers also included the mother, a sister (both without abnormalities), and a nephew (with episodic pains in his feet). We conclude that familial chronic renal failure combined with proteinuria is suggestive of Fabry disease, and such specific mutations as E66K predominantly may affect the kidneys.

Topics: Adult; Amino Acid Substitution; Child; Creatinine; Diagnosis, Differential; Fabry Disease; Female; Humans; Hypertension; Kidney; Kidney Failure, Chronic; Male; Middle Aged; Mutation, Missense; Obesity; Pedigree; Point Mutation; Proteinuria; Trihexosylceramides

Urine specimens from two sibs affected with cerebroside sulfatase activator deficiency were examined to ascertain whether the deficiency of the supplementary activator protein required for the enzymatic hydrolysis of cerebroside sulfate was also evident in urine. Material from chromatographic fractionations was examined for the activator activity to avoid ambiguities resulting from protein inhibition. There were substantial deficits in all chromatographic fractions corresponding to activator-containing fractions of control urines. Since patient urines contained elevated amounts of lactosylceramide, digalactosylceramide, and globotriaosylceramide and since similarities between activators for cerebroside sulfate and GM1 ganglioside hydrolyses had been noted previously, the chromatographic fractions were also examined for activators in other glycosphingolipid hydrolase systems. There was coincidence of activators for the GM1 ganglioside/beta-galactosidase and the globotriaosylceramide/alpha-galactosidase A reactions with the cerebroside sulfatase activator in control urine fractions, and the patients' urines were deficient in activator activities for the three reactions. Identity of the three activators was suggested and antiserum to purified GM1 ganglioside activator was used to test this possibility. There were depressed levels of cross-reacting material in fractions of patient urines by Ouchterlony double diffusion and in unfractionated urine by enzyme-linked immunosorbent assay. Purified activators for the cerebroside sulfate and GM1 ganglioside systems showed lines of identity with no spurring on Ouchterlony double diffusion, identical mobility on immunoelectrophoresis, and similar stimulatory activities toward hydrolysis of the three glycosphingolipid species by their respective enzymes. Finally, the three activator activities were retained by anti-GM1-activator IgG coupled to Sepharose 4B. The results suggest strongly that the same protein entity serves as activator for the enzymatic hydrolysis of cerebroside sulfate, GM1 ganglioside, and globotriaosylceramide.

Topics: alpha-Galactosidase; Animals; beta-Galactosidase; beta-N-Acetylhexosaminidases; Enzyme Activation; G(M1) Ganglioside; G(M2) Ganglioside; Gangliosides; Globosides; Glycosphingolipids; Hexosaminidases; Humans; Hydrolysis; Immunodiffusion; Immunosorbent Techniques; Protein Deficiency; Proteins; Proteinuria; Rats; Saposins; Trihexosylceramides