What are the renal manifestations in Fabry disease?

Renal Manifestations in Fabry Disease

In Fabry disease, the kidneys show progressive accumulation of globotriaosylceramide (GL-3) in multiple cell types, particularly in podocytes, distal tubular epithelial cells, vascular endothelium, and mesangial cells, leading to proteinuria and eventual end-stage renal disease. 1

Pathophysiology of Renal Involvement

• The primary pathological feature is the accumulation of GL-3 in lysosomes of various renal cell types, creating electron-dense vesicles visible on electron microscopy 1
• Vascular endothelial cells show prominent GL-3 deposits, contributing to ischemia and infarction of small vessels in the kidney 1
• Early and substantial deposition occurs in podocytes, which leads to proteinuria 1
• Distal tubular epithelium and loop of Henle cells show dense GL-3 accumulations 2
• Mesangial cells and interstitial cells of the renal cortex also accumulate GL-3 3
• Mitochondrial dysfunction occurs in renal tubular cells, with fragmented mitochondria showing disrupted cristae structure and elevated oxidative stress levels 4

Clinical Manifestations

• Mild proteinuria typically begins in childhood or adolescence 1
• Progressive decline in glomerular filtration rate (GFR) occurs with age 2
• End-stage renal disease typically develops by the third to fifth decades of life in males with classic disease 3
• Renal manifestations may be less severe in heterozygous females but can still progress to significant kidney disease due to random X-chromosomal inactivation 1
• Hypertension may develop as kidney function deteriorates 5

Diagnostic Findings

• Urinalysis shows proteinuria, which may present as foamy urine 6
• Electron microscopy of kidney biopsies reveals characteristic GL-3 inclusions in various cell types 1
• Light microscopy with semi-quantitative scoring can assess the degree of GL-3 inclusions in renal interstitial capillaries (scale 0-3) 7
• Reduced GFR and increased protein-to-creatinine ratio are common laboratory findings 7
• Increased carotid intima-media thickness may be associated with kidney involvement, particularly in patients with elevated plasma lysoGb3 levels 5

Treatment Effects on Renal Pathology

• Enzyme replacement therapy (ERT) with recombinant human α-galactosidase A has been shown to clear GL-3 deposits from various renal cell types 7
• Complete clearance occurs in vascular endothelium, mesangial cells, and interstitial cells after treatment 3
• Moderate clearance is observed in smooth muscle cells of arterioles and small arteries 3
• Podocytes and distal tubular epithelium show more limited clearance compared to other cell types 3
• Early initiation of ERT may be more effective in stabilizing renal function or slowing its decline compared to starting therapy in advanced disease 2

Monitoring and Follow-up

• Regular assessment of proteinuria and GFR is essential to monitor disease progression 2
• Kidney biopsies may be used to evaluate GL-3 clearance in response to treatment 7
• Monitoring for cardiovascular complications is important as patients with renal Fabry disease are at increased risk of cardiovascular events 2
• The rate of decline in renal function (eGFR slope) can be used to assess treatment efficacy 7

Clinical Pearls and Pitfalls

• Fabry disease is often underdiagnosed due to nonspecific and multiorgan symptoms 8
• Renal manifestations may be mistakenly attributed to other causes of chronic kidney disease 8
• Timely diagnosis and early initiation of ERT are crucial for preventing irreversible kidney damage 2
• Even with ERT, some patients may still progress to end-stage renal disease, requiring dialysis or transplantation 1
• The presence of proteinuria at baseline is a predictor of faster progression of renal disease 2