OVERVIEW
Thin basement membrane nephropathy was first reported in 1966 by McConcille et al. In 1973, Rogers et al. were the first to reveal the pathologic features of the disease by observing diffuse thinning of the glomerular basement membrane (GBM) in patients with the disease under an electron microscope. Thin basement membrane nephropathy is a group of diseases with histologic manifestations of glomerular basement membrane thinning, clinically characterized by glomerulonephritis, but genetically without gene mutation. It is classified as benign and progressive according to the presence or absence of progressive renal impairment, and as familial and sporadic according to the presence or absence of family history.
The prevalence of the disease has been variably reported, with estimates as high as 5% to 9%, accounting for approximately 20% of primary asymptomatic hematuria. The disease can occur at any age, with equal chances of occurrence in men and women. The majority of cases occur below 40 years of age, with isolated reports of cases detected at 80 years of age or older.
Etiology
The disease is usually inherited in an autosomal dominant manner, but in recent years, autosomal recessive families have also been found. Recently, Smeets et al. found that the mutated genes are also COL4A3 and COL4A4, which are located on autosomal chromosome 2. Why some COL4A3 and COL4A4 mutations cause hereditary progressive nephritis while others cause familial benign hematuria remains to be investigated. Some authors have used specific antibodies against Goodpasture syndrome antigens to stain the GBM of this disease and were able to color it, suggesting that the changes in collagen IV in this disease are different from those in hereditary progressive nephritis.
Classification
If a patient has glomerular basement membrane thinning and a family history of the disease without progressive renal impairment, the disease is called benign familial thin basement membrane nephropathy, or familial benign hematuria, and others call it nonprogressive hereditary nephritis. This is the most common type of thin basement membrane nephropathy. Thin basement membrane nephropathy is divided into:
1. familial thin basement membrane nephropathy, benign familial thin basement membrane nephropathy, and progressive thin basement membrane nephropathy.
2. sporadic thin basement membrane nephropathy, benign thin basement membrane nephropathy, progressive thin basement membrane nephropathy.
Symptoms
The clinical manifestations of the disease are similar to those of Olport’s syndrome. The most prominent finding in various thin basement membrane nephropathies is microscopic hematuria. Usually hematuria begins in childhood and in some cases in adulthood. Hematuria is usually persistent, but in some patients it is intermittent, and in these patients it appears to persist into old age. Episodic hematuria is often associated with infection. Nasal hematuria is evident after upper respiratory tract infections or strenuous exercise. Patients usually have no proteinuria, edema, or hypertension, and renal function is always normal; there is also no neurodeafness or ocular abnormalities.
Most patients with thin basement membrane nephropathy, including familial benign hematuria, do not have significant proteinuria.
Examination
1. Laboratory tests
Blood complement, plasma protein electrophoresis, antinuclear antibodies, platelet count, urea nitrogen, creatinine are normal. Patients may have hematuria, urine erythrocyte phase microscopy for the size of the glomerulonephritic red blood cells in a variety of forms, about 1/3 of the patients have erythrocyte tubular pattern. However, there is no obvious proteinuria and nephrotic syndrome.
2. Other auxiliary examinations
(1) Light microscopy Usually there is no abnormal finding, the glomeruli are usually normal under light microscopy, and the tubular pattern of erythrocytes is present in the renal tubules. Occasionally, some non-specific minor glomerular changes, such as mild thylakoid hyperplasia, can be seen, which has no diagnostic significance. There have also been some reports of finding globular glomerulosclerosis, focal tubular atrophy, mild thylakoid widening and immature glomeruli.
(2) Immunofluorescence Immunoglobulins and complement are usually negative in the glomeruli of patients with this disease, and small amounts of IgG, IgM, IgA, and C3 have been reported to be deposited along the glomerular basement membrane. Binding of autoantibodies against the glomerular basement membrane, as well as the ability to bind monoclonal antibodies against the Gudpaschus antigen, is normal or slightly reduced.
(3) Ultrastructure The main ultrastructural feature is the thinning of the glomerular basement membrane. Under the electron microscope, the characteristic changes of this disease can be seen: diffuse thinning of the GBM, the thickness of the GBM is only 1/3 to 2/3 of the normal thickness or even thinner, and there is no thickening and splitting of the GBM segments. In some families individual adult patients have normal glomerular basement membrane thickness, while other members of the family have thin glomerular basement membranes. In some families presenting with familial benign hematuria, the glomerular basement membrane thickness is normal. Even in families where glomerular basement membrane thinning is present, not all vascular loops have thinned walls. In patients of all ages with this disease, parietal thickening of the tunica albuginea may be found, associated with focal capillary wall rupture. In a few cases, segmental irregularities of the vascular contour and deposits of granular material in the meninges may be found.
Diagnosis
In any young adult patient presenting clinically with asymptomatic hematuria (predominantly persistent or intermittent microscopic hematuria) with a positive family history (autosomal dominant or recessive), renal biopsy electron microscopy should be considered if it reveals diffuse GBM thinning. However, the discovery of glomerular basement membrane thinning is not equivalent to the diagnosis of thin basement membrane nephropathy, there must be a renal biopsy showing no separation of the dense layer of the glomerular basement membrane and laminar changes, in order to make a diagnosis of this disease.
Further diagnosis of benign familial thin basement membrane nephropathy (familial benign hematuria) should be made with caution. The diagnosis can only be established if there is no progression of renal disease after years of follow-up and a renal biopsy shows no separation of the dense layer of the glomerular basement membrane and no laminar changes. Patients diagnosed with this disease should undergo regular nephrological examinations, especially for the presence of urinary protein, and ideally, urinalysis should be performed on family members.
Key points in the diagnosis of this disease
1. Age of onset
Thin basement membrane nephropathy can occur at any age, with the youngest reported to be 1 year old and the oldest 86 years old.
2. Symptoms
Most patients are asymptomatic, or occasionally found microscopic hematuria, no or mild proteinuria, normal blood pressure and renal function. Nasal hematuria and proteinuria appear during or after upper respiratory tract infections or after strenuous exercise. Rarely, recurrent low back pain similar to IgA nephropathy is the first symptom.
3.Laboratory Tests
Blood complement, plasma protein electrophoresis, antinuclear antibody, platelet count, urea nitrogen, creatinine are all normal, patients with urinary erythrocytes bitemporal microscopy for the size of the glomerulonephritic cells, a variety of forms of glomerular origin of red blood cells, about 1/3 of the patients with erythrocyte tubular pattern.
4. Renal biopsy
Light microscopy is normal or mildly abnormal, glomerular mesangium is mildly to moderately hyperplastic, immunofluorescence is negative, and electron microscopy shows only diffuse thinning of the GBM without electron dense deposition, which is the only or the most important pathologic feature of this disease. The width of normal basement membrane is 300～400nm, but in this disease, the width of basement membrane is only 150～225nm, and the thinnest glomerular basement membrane is 110nm, which is 1/3～2/3 of that of normal people.According to the above points, the diagnosis of thin basement membrane nephropathy can be established.
Differential diagnosis
1. Alport syndrome (hereditary nephritis)
Due to the similarity of early histology, thin basement membrane nephropathy may be difficult to distinguish from hereditary nephritis. Alport syndrome is usually seen only in adolescents, with progressive renal hypoplasia, which is more severe in males, such as deafness, ophthalmopathy, and familial hematuria and progressive renal hypoplasia, suggesting that Alport syndrome may be present. Patients with thin basement membrane nephropathy do not have typical extrarenal manifestations or significant renal failure and family history. Electron microscopy of Alport syndrome GBM thickening and multilayered structure can form a mesh, which contains dense particles accompanied by segmental GBM thinning; thin basement membrane nephropathy diffuse GBM thinning without electron dense material deposition. Therefore, it should not be too difficult to differentiate between the two diseases. However, benign familial thin basement membrane nephropathy can coexist with deafness, therefore, renal biopsy should be performed to clarify the absence of separation of the dense layer of the glomerular basement membrane and laminar changes, and if there is, then the diagnosis is Olport’s syndrome.
The presence of significant proteinuria in patients diagnosed with thin basement membrane nephropathy, especially when accompanied by hypertension or renal insufficiency, suggests that the patient is not benign familial thin basement membrane nephropathy and should be considered to have progressive thin basement membrane nephropathy; or suggests that the patient may be suffering from other diseases, such as IgA nephropathy or familial membranoproliferative glomerulonephritis. Repeat renal biopsy is needed to observe whether the dense layer of glomerular basement membrane is separated and laminar changes.
2. Tethered membrane IgA nephropathy
Patients with IgA nephropathy with hematuria as the main clinical manifestation often do not have a family history of hematuria. Immunofluorescence of renal biopsy showed IgA-based immunoglobulin deposition, and electron microscopy showed large electron dense material deposition, which made it not difficult to distinguish tethered membrane IgA nephropathy from thin basement membrane nephropathy. Recently, there is a report of a family with thin basement membrane nephropathy combined with mesangial IgA nephropathy, which should be noted and further discussed.
3. Other diseases
Thin basement membrane nephropathy must be distinguished from surgical hematuria (e.g., stones, tumors, tuberculosis, etc.), urinary tract infections, certain primary glomerular diseases (e.g., thylakoid proliferative nephritis, acute post-streptococcal nephritis) and secondary glomerular diseases (e.g., purpura nephritis, lupus nephritis, vasculitis nephritis), which are characterized by hematuria as the main manifestation of hematuria. They can be excluded on the basis of the clinical features of each of the above diseases laboratory tests and pathologic changes.
Treatment
Thin basement membrane nephropathy is a benign disease that requires no specific treatment. For a few patients with symptoms of hypertension, blood pressure should be controlled in time, but unnecessary treatment and application of nephrotoxic drugs should be avoided; when episodic hematuria occurs, attention should be paid to the presence or absence of upper respiratory tract infections, and appropriate treatment is feasible. For the progressive thin basement membrane nephropathy, symptomatic treatment should be carried out; a small number of patients with progressive renal failure, as well as recurrent hematuria, proteinuria and lumbago, angiotensin-converting enzyme inhibitors, angiotensin receptor antagonists can be given treatment. A definite protein-lowering effect has been reported with ACEI analogs. In addition, a low-protein diet and Chinese medicines with protein-lowering effects, such as renal hepatic ning and formulas containing Beiqiqi, can be given; hypertension and chronic renal insufficiency should be treated according to the appropriate therapeutic principles.
Prevention
There is no special treatment for this disease, and avoiding cold and excessive fatigue is necessary. It has been reported in the literature that very few cases of hematuria and erythrocyte tubular pattern, or proteinuria should be alerted and should be treated symptomatically. It is better to use traditional Chinese medicine for diagnosis and treatment to prevent slow onset of renal insufficiency.