What is Thin Basement Membrane Nephropathy?
Thin basement membrane nephropathy (TBMN), also known as thin basement membrane disease, is a common but often underdiagnosed reason for blood in the urine (glomerular bleeding) in both children and adults. This is a genetic disorder often found in families, caused by changes (mutations) in the genes responsible for different parts of a protein called type IV collagen. This protein is a key element in a crucial part of the kidney called the glomerular basement membrane (GBM).
In the past, TBMN was referred to as benign familial hematuria. However, this term is no longer used because our understanding of the genetic causes and various ways this condition may show itself (clinical presentation) has improved. Other older terms that are no longer used include “benign persistent hematuria,” and “benign essential hematuria.”
TBMN is identified by a widespread thinning of the GBM, detectable through a kidney biopsy. It mainly presents as microscopic blood in the urine in most cases. However, other symptoms such as protein in the urine (proteinuria), high blood pressure (hypertension), and varying levels of kidney function impairment may also be observed.
TBMN shares some similarities with Alport syndrome. They both result from mutations in type IV collagen genes. However, unlike Alport syndrome, especially its common X-linked variant, TBMN doesn’t have symptoms that affect other parts of the body (extrarenal features). For more information on Alport syndrome, consider referring to another StatPearls’ resource titled “Alport Syndrome.”
What Causes Thin Basement Membrane Nephropathy?
The conditions known as TBMN are caused by changes, or mutations, in two genes named COL4A3 and COL4A4. These genes are found on a specific location on chromosome 2, designated as 2q35-37. Their role is to guide the creation of two different parts of a protein called type IV collagen.
These mutations only affect one of the two copies of the gene, a situation that is called heterozygous. The mutations can take on several forms, including changes that affect how the gene’s instructions are read (called splice variants), changes that cause a different amino acid to be added into the protein (called missense mutations), or changes that can throw off the whole sequence of amino acids in the protein (called frameshift mutations).
Between half and two-thirds of the patients showing TBMN also have a family member with the condition, suggesting an inheritance pattern that passes the condition from parent to child (referred to as autosomal dominant). However, some patients may have developed the mutation ‘out of the blue’ without inheritance, known as a de novo mutation. The condition can also sometimes not fully express itself in a person even though they have the gene mutation, a phenomenon known as incomplete penetrance. This might be why some people with the mutation don’t show a family history of the condition.
Risk Factors and Frequency for Thin Basement Membrane Nephropathy
Thin Basement Membrane Nephropathy (TBMN), a common cause of blood in the urine, can affect both adults and children. The typical age of diagnosis varies greatly, with the median age being 37 for adults and 7 for children. It’s noted that TBMN is more frequently seen in females and is not influenced by a person’s ethnicity.
It’s tricky to know exactly how many people are affected by TBMN. This is because the symptoms can vary from person to person, and in many cases, it likely goes unnoticed. Some studies suggest that around 5% to 9% of the general population display signs of the condition, based on examinations of kidneys that were transplanted. However, more cautious estimates suggest the occurrence of TBMN is between 1% and 2%.
Signs and Symptoms of Thin Basement Membrane Nephropathy
Thin basement membrane nephropathy (TBMN) is usually first discovered when someone has a medical test for something else, and it turns out that they have little amounts of blood in their urine – a condition known as microscopic hematuria. When this happens, the patient’s medical history and physical examination usually show no other issues. Sometimes, the patient may have relatives with the same condition, but it’s also possible that they don’t.
Blood that you can see in the urine (gross hematuria) or “cola-colored” urine is less common in TBMN. This is seen in 5% to 22% of TBMN cases and more often in kids, particularly after infection or physical activity. Protein in the urine (proteinuria) isn’t usually present, but can become more likely as the patient gets older. When it does occur, it is usually in small amounts, below 3000 mg of protein per 24 hours. A related condition that’s often seen in patients with TBMN is high blood pressure.
In evaluating a patient for TBMN, doctors focus on identifying any potential or obvious causes of microscopic hematuria. The medical history review is aimed at ruling out other common illnesses such as conditions of the urinary tract, kidney stones, and IgA nephropathy. A detailed review of symptoms is important to rule out systemic symptoms of autoimmune diseases like lupus, which can also present with microscopic hematuria.
- Most patients with TBMN have relatives with the same condition but without serious kidney disease progression.
- Having blood in the urine with no urinary tract problems highly suggests TBMN.
- A specific history of hearing loss and eye lesions could help differentiate TBMN from another kidney disease called Alport syndrome.
Investigating family medical history is vital to identify potential family cases of TBMN, differentiate it from Alport syndrome, and predict the disease course. Doctors ask about family incidences of blood in urine, hearing or vision loss, and crucially, any history of progressive kidney disease or dialysis dependence in family members. During a physical examination, the focus is on measuring blood pressure, checking for swelling that could indicate proteinuria, and conducting a careful assessment of vision and hearing. Additionally, doctors look out for systemic signs such as a rash or joint problems, which could suggest other possible causes of glomerular hematuria.
It’s noteworthy that patients with TBMN from certain geographical areas can exhibit different clinical signs. For example, a patient cluster from Cyprus was found to have a more progressive type of TBMN, with 14% out of 127 patients developing serious kidney disease. When evaluating and managing TBMN, such geographical clusters should be taken into account.
Testing for Thin Basement Membrane Nephropathy
When you see your doctor suspecting Thin basement membrane nephropathy (TBMN), a type of kidney disease, a few initial steps are taken to make a diagnosis. First, a urinalysis is done. This is a simple test that checks the concentration of your urine and looks for any abnormalities. Additionally, your doctor will perform a microscopic examination of your urine and an evaluation of your kidney function.
For patients with TBMN, the urinalysis usually reveals blood in the urine (hematuria) that’s not visible to the naked eye. If there’s too much protein in the urine (proteinuria), it’s also noted. If this is found, the protein levels in your urine need to be measured more precisely. This is usually done by analyzing a sample of your urine – the so-called spot urine sample – and measuring the amount of protein relative to the amount of a substance called creatinine. Less than 0.2 is normal, while anything 0.3 or higher is considered abnormal.
Next, a microscopic examination of your urine sediment could reveal irregularly shaped red blood cells (RBCs) or clumps of red blood cells (RBC casts), both of which can suggest kidney damage. But even if these are not found, it doesn’t necessarily mean you don’t have kidney damage.
Finally, to check how well your kidneys are working, your doctor will test the levels of substances like creatinine and blood urea nitrogen in your bloodstream. If proteinuria is found, the doctor will also measure your albumin (a type of protein) levels to see if there might be a severe kidney disease called nephrotic syndrome.
In some cases, a kidney biopsy – a procedure in which a small sample of kidney tissue is removed for further testing – might be recommended. This usually happens when additional symptoms, suggest a more severe kidney damage, or if there’s a family history of kidney disease or associated genetic conditions.
Even though genetic testing is not commonly required, it can be performed if needed. This involves looking for mutations in genes called COL4A3 and COL4A4, which are associated with TBMN. However, these mutations are often not found in patients that only show microscopic hematuria. The chance of detecting such a mutation increases if there are impairments in kidney function or a family history of this disease.
In certain instances, a genetic test for a related kidney disease called X-linked Alport syndrome might be necessary, especially when family history and kidney biopsy findings suggest it. This is because this similar disease sometimes presents itself as TBMN.
Treatment Options for Thin Basement Membrane Nephropathy
There isn’t a specific treatment plan for Thin Basement Membrane Nephropathy (TBMN), a condition that affects your kidneys and is often identified by small amounts of blood in your urine. Most people with TBMN have a good prognosis and don’t need a formal treatment plan.
However, if you’re diagnosed with TBMN, your doctor will likely keep an eye on you, watching for signs of high blood pressure. Regular check-ups may include routine blood pressure measurements and several lab tests like serum creatinine and blood urea nitrogen tests. These can help monitor for any decrease in kidney function. Urine tests are also important to keep track of any signs of protein in the urine. Your doctor can do these routine checks and will refer you to a specialist if necessary.
Your doctor will offer suggestions for managing TBMN if they start seeing signs of protein in your urine or high blood pressure. These suggestions could include managing your blood pressure to keep it under 130/80 mm Hg (in line with guidelines by the American College of Cardiology/American Heart Association), reducing your salt intake to less than 2000 mg of sodium a day, and encouraging regular physical activity, around 150 minutes per week. Prescription medication might also be suggested to help maintain a healthy balance in your body’s renin-angiotensin system.
The use of medications that suppress the immune system is not necessary for managing TBMN.
If you start treatment for high blood pressure or protein in the urine, or if your doctor notices your kidney function deteriorating, you’ll need to have more frequent check-ups. This will allow your doctor to manage any complications that might arise, like chronic kidney disease, anemia caused by chronic kidney disease, CKD-related mineral and bone disorders, and end-stage renal disease. You’ll be advised to visit a nephrologist, a doctor who specializes in kidney care, to manage these issues.
Genetic counseling can be beneficial for TBMN patients and their families. This can help you understand your diagnosis, the likely inherited nature of TBMN, and the need for continued monitoring of the disease.
In terms of kidney donation, individuals with TBMN used to be considered acceptable kidney donors because some people with TBMN have not experienced significant issues or complications after receiving a kidney transplant. However, due to better understanding of the relationship between TBMN and some forms of Alport syndrome (a genetic condition that can affect kidney function), those with mutations in specific genes (COL4A3 or COL4A4) are now advised not to consider being a kidney donor.
What else can Thin Basement Membrane Nephropathy be?
Alport Syndrome is very similar to TBMN (Thin Basement Membrane Nephropathy), so it’s essential to tell them apart due to their varying outcomes. Alport syndrome seems to be the most recognized form and can be passed down through generations dominantly, recessively, and X-linked manners due to changes in certain genes. On the other hand, TBMN is usually inherited in a dominant manner due to changes in two different genes. Key differences between these two conditions include:
- Mutations and inheritance: The most well-recognized form of Alport syndrome is caused by mutations in COL4A5 and is usually inherited in an X-linked manner. However, Alport syndrome can follow autosomal recessive or autosomal dominant inheritance patterns due to mutations in COL4A3 and COL4A4. As compared to Alports, TBMN is mostly inherited through an autosomal dominant pattern, usually due to mutations in COL4A3 or COL4A4.
- Pathology: TBMN’s key feature is a uniformly thin renal membrane, observed in more than half the membrane, while Alport syndrome features irregularities and varying thickness of the renal membrane, inclusive of small, dense “breadcrumb” buildup between layers. A combination of microscopic and immunohistology tests on the kidney can aid in accurate diagnosis.
- Symptoms: Males with X-linked Alport syndrome typically show early signs of hearing loss, vision changes, and a high risk of harmful kidney disease progression. Female carriers usually have mild symptoms and a lower kidney disease progression risk. Both TMBN and autosomal Alport syndrome typically do not exhibit kidney disease and their risk of worsening to harmful kidney disease depends on the existence of proteinuria and a positive family history of kidney disease.
- Treatment: Neither Alport syndrome nor TBMN can be cured. Approved pharmaceutical therapies only apply when proteinuria is present, known as ACE inhibitors or ARB.
There is no role for immunosuppression in either conditions. At this time, potential new agents are being tested for Alport syndrome but they have not been officially approved yet. On the other hand, no potential agents are being tested for TBMN. - Outlook: The X-linked form of Alport syndrome generally has a poor outlook, with approximately half of affected males developing end-stage renal disease by age 30 and about 90% by age 40. For females with X-linked Alport syndrome, the outlook is better with a 25% lifetime risk of progression. Both the autosomal recessive Alport syndrome forms generally have a poor prognosis, with most patients reaching ESRD by age 30. Comparatively, autosomal dominant forms of Alport syndrome and TBMN have similar prognosis. They have a less than 1% estimated risk of progressing to ESRD, unless proteinuria or a significant family history is present, which can increase the risk up to 20%.
In conclusion, due to their shared molecular cause and overlapping symptoms, it has been suggested that both Alport syndrome and TBMN should be recognized under type IV collagen disorders.
Other conditions to consider when diagnosing TMBN include:
- IgA nephropathy
- Postinfectious glomerulonephritis
- Lupus nephritis
- Medullary sponge kidney
Urological conditions like cancer and kidney stones should also be considered when diagnosing isolated microscopic hematuria. For patients under 50 years old with asymptomatic microscopic hematuria and no identified urological reason, it is advisable to consult a nephrologist. This becomes especially important if the patient shows persistent proteinuria, an abnormal serum creatinine level, unusual red blood cells in urine, worsening high blood pressure, increasing swelling, or a family history of kidney disease.
What to expect with Thin Basement Membrane Nephropathy
The long-term outlook for most people with Thin Basement Membrane Nephropathy (TBMN), a condition affecting the kidneys, is generally favorable. In most cases, TBMN doesn’t lead to the worsening of kidney disease or to End-Stage Renal Disease (ESRD), a severe form of chronic kidney disease where the kidneys have stopped working as they should.
However, our understanding of TBMN’s genetic basis, its connections with other kidney conditions involving mutations in the genes COL4A3 and COL4A4 (like Alport syndrome, variants of a condition called IgA nephropathy, and focal segmental glomerulosclerosis) has evolved. This has led to a change in perspective, and TBMN isn’t always seen as a harmless condition that needs no monitoring anymore. Hence, naming TBMN as “benign familial hematuria” is no longer recommended, and the terms “thin basement membrane disease/nephropathy” or “TBMN” are preferred.
The estimated risk of someone with TBMN developing ESRD is usually less than 1%, especially if they don’t have associated risk factors. But, if they do have risk factors like high levels of protein in their urine, signs of kidney dysfunction, certain biopsy results (for example, changes like focal segmental glomerulosclerosis, a thickening of the kidney tissue, and a layered appearance), or a family history of progressive kidney disease, their risk of developing ESRD can increase up to 20%.
Possible Complications When Diagnosed with Thin Basement Membrane Nephropathy
The problems associated with TBMN are elevated blood pressure, an excess of protein in the urine, and stage 5 kidney disease. However, these are rarely seen. Also noteworthy are the emotional and social effects like anxiety following the diagnosis, especially in young people, and possible problems arising from undergoing genetic tests without suitable advice. We also need to consider complications that might occur from medical tests like kidney biopsies.
To avoid these complications, it’s crucial to understand the patient’s complete medical history, including information about health problems in the family, provide advice related to genetic testing, and decide carefully which patients should be genetically tested or have a kidney biopsy.
Typical Complications:
- Elevated blood pressure
- Excess of protein in the urine
- Stage 5 Kidney disease
- Anxiety following diagnosis
- Issues from genetic tests without proper advice
- Complications from kidney biopsy
Prevention Measures:
- Understanding the patient’s complete medical history
- Offering advice on genetic testing
- Carefully determining who should undergo genetic testing or renal biopsy
Preventing Thin Basement Membrane Nephropathy
TBMN is a condition that is passed down through families, meaning it’s genetic. This also means that we can’t prevent TBMN from happening. It’s important that people with TBMN understand it’s a genetic disease that is usually inherited from a parent, but in some rare cases, it can occur for the first time in a family.
People with this condition should be mindful to regularly check their blood pressure, test for protein in their urine, and monitor their kidney function. They should also take part in genetic counseling, which can provide them with more information about this inherited condition.
While it’s generally a mild disease, it’s important that patients don’t worry too much about it. But at the same time, patients need to be aware of certain things that may make their kidney disease worse, and lead to ESRD (End-Stage Renal Disease). ESRD is a severe condition that may require dialysis, a treatment to clean waste and extra fluid from the blood when the kidneys can’t do this task anymore.
