Fibronectin glomerulopathy

Other names:familial glomerular nephritis with fibronectin deposits;familial lobular glomerulopathy;GFND;glomerulopathy with fibronectin deposits;glomerulopathy with giant fibrillar deposits

Fibronectin glomerulopathy is a kidney disease that usually develops between early and mid-adulthood but can occur at any age. It eventually leads to irreversible kidney failure (end-stage renal disease).

Epidemiology

Fibronectin glomerulopathy is likely a rare condition, although its prevalence is unknown. At least 45 cases have been described in the scientific literature.

Cause

Fibronectin glomerulopathy can be caused by mutations in the FN1 gene. The FN1 gene provides instructions for making the fibronectin-1 protein. Fibronectin-1 is involved in the continual formation of the extracellular matrix, which is an intricate lattice of proteins and other molecules that forms in the spaces between cells. During extracellular matrix formation, fibronectin-1 helps individual cells expand (spread) and move (migrate) to cover more space, and it also influences cell shape and maturation (differentiation).

FN1 gene mutations lead to production of an abnormal fibronectin-1 protein that gets deposited in the glomeruli of the kidneys, probably as the body attempts to filter it out as waste. Even though there is an abundance of fibronectin-1 in the glomeruli, the extracellular matrix that supports the blood vessels is weak because the altered fibronectin-1 cannot assist in the matrix's continual formation. Without a strong cellular support network, the glomeruli are less able to filter waste. As a result, products that normally are retained by the body, such as protein and blood, get released in the urine, and acids are not properly filtered from the blood. Over time, the kidneys' ability to filter waste decreases until the kidneys can no longer function, resulting in end-stage renal disease. It is estimated that mutations in the FN1 gene are responsible for 40 percent of cases of fibronectin glomerulopathy. The cause of the remaining cases of this condition is unknown.

Inheritance

Autosomal dominant pattern, a 50/50 chance.

When fibronectin glomerulopathy is caused by mutations in the FN1 gene, it is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. In some of these cases, an affected person inherits the mutation from one affected parent. Other cases result from new mutations in the gene and occur in people with no history of the disorder in their family. Some people who have the altered FN1 gene never develop the condition, a situation known as reduced penetrance.

Signs and symptoms

Individuals with fibronectin glomerulopathy usually have blood and excess protein in their urine (hematuria and proteinuria, respectively). They also have high blood pressure (hypertension). Some affected individuals develop renal tubular acidosis, which occurs when the kidneys are unable to remove enough acid from the body and the blood becomes too acidic. The kidneys of people with fibronectin glomerulopathy have large deposits of the protein fibronectin-1 in structures called glomeruli. These structures are clusters of tiny blood vessels in the kidneys that filter waste products from blood. The waste products are then released in urine. The fibronectin-1 deposits impair the glomeruli's filtration ability. Fifteen to 20 years following the appearance of signs and symptoms, individuals with fibronectin glomerulopathy often develop end-stage renal disease. Affected individuals may receive treatment in the form of a kidney transplant; in some cases, fibronectin glomerulopathy comes back (recurs) following transplantation.

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. 80%-99% of people have these symptoms

• Glomerulopathy
• Hypertension
• Hypoalbuminemia(Low blood albumin)
• Mesangial abnormality
• Microscopic hematuria(Small amount of blood in urine)
• Nephrotic syndrome
• Pedal edema(Fluid accumulation in lower limbs)
• Proteinuria(High urine protein levels)
• Renal insufficiency(Renal failure)

5%-29% of people have these symptoms

• Cerebral hemorrhage(Bleeding in brain)

Diagnosis

Diagnosis rests on renal biopsy. Typical findings at light microscopy are enlarged glomeruli with deposits in the mesangium and subendothelial space, usually with scant immunoreactivity for immunoglobulins or complement factors. Electron microscopy reveals deposits mainly located in the subendothelial space but also in the subepithelial and intramembranous spaces. Homogeneous granular deposits dominate in most cases; in some an admixture of fibrils is observed. The most striking finding is the immunoreactivity of the glomerular deposits to fibronectin. Family history is supportive of the diagnosis.

Differential diagnosis Differential diagnosis includes other chronic non-amyloid glomerulopathies with organized deposits including mixed cryoglobulinemia, fibrillary glomerulonephritis, immunotactoid glomerulopathy, collagen type III glomerulopathy, systemic lupus erythematosus, diabetes glomerulopathy and other non-specific collagen deposition diseases. It is difficult to discriminate fibronectin glomerulopathy from membranoproliferative glomerulonephritis at light microscopy examination.

Treatment

There is no specific treatment for fibronectin glomerulopathy. Treatment of symptoms can include corticosteroids, diuretics and treatment for hypertension. Antiproteinuric and renoprotective treatment with ACE inhibitors or anti-AT1R antagonists could be of help to slow renal disease progression. More advanced cases of renal failure require renal dialysis or transplantation.

Prognosis

Prognosis is uncertain, in some cases the disease follows an indolent course and in others it leads to end stage renal disease and chronic renal failure in the second to sixth decade of life.

NIH genetic and rare disease info

• NIH info on Fibronectin glomerulopathy

Fibronectin glomerulopathy is a rare disease.

Fibronectin glomerulopathy Resources
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