Membranous Nephropathy

What is Membranous Nephropathy?

Membranous nephropathy, often referred to as membranous glomerulopathy, is a type of kidney disorder. It causes a condition known as nephrotic syndrome, which includes a variety of symptoms. These can include swelling in the arms and legs (peripheral edema), high blood pressure, frothy urine (excessive bubbles in the urine), and signs of blood clots.

One significant symptom is a considerable amount of protein (over 3.5 grams per day) being lost in the urine, which is called proteinuria. Lab tests for this condition often show low levels of albumin (a type of protein) in the blood, high levels of fat in the blood (dyslipidemia), and potential signs of kidney damage such as high creatinine levels. Unlike other kidney conditions, membranous nephropathy doesn’t involve blood or blood cell fragments in the urine.

This type of kidney damage is caused by injury to specific cells in the kidney (podocytes) and the loss of a protective barrier in the kidneys. This results in albumin (a type of protein in your blood) ending up in the urine. This is different from other kidney conditions known as nephritic syndromes, where inflammation in a part of the kidney (the glomerular basement membrane) plays a major role.

What Causes Membranous Nephropathy?

Membranous nephropathy is a kidney disease. It is split into two categories, Primary and Secondary.

Primary membranous nephropathy makes up roughly 75-80% of cases. It isn’t fully understood, but we have found some clues. For 70-80% of these cases, we can trace the disease back to antibodies which fight against a particular protein, called the phospholipase A2 receptor antigen, linked to the HLA DQA1 gene. In 15-20% of cases, it’s associated with antibodies fighting against a neurological protein known as NELL. For 1-5% of cases, the disease is linked to antibodies that target a protein called thrombospondin. Lastly, in some rare instances, it is associated with antibodies against proteins known as neutral endopeptidase and exostosin. What’s important to remember is that these cases are all considered “primary” because they can’t be tied to another condition.

Secondary membranous nephropathy makes up the other 20-25% of cases. For these situations, another disease or condition is what leads to the kidney damage. This can include infections like hepatitis B, hepatitis C, syphilis, malaria, HIV, and schistosomiasis; cancers like adenocarcinoma, squamous cell carcinoma, and hematological malignancies; exposure to certain medications like non-steroidal anti-inflammatory drugs, anti-tumor necrosis factor-alpha inhibitors, penicillamine, and probenecid. Even poisoning by heavy metals like gold and mercury can cause secondary membranous nephropathy. Finally, autoimmune diseases such as lupus, Sjogren’s syndrome, rheumatoid arthritis, and IgG4 can lead to this issue, along with other miscellaneous reasons like receiving a stem cell transplant, or having diabetes. In each of these cases, addressing the root disease or condition is key to treating the kidney disease.

Risk Factors and Frequency for Membranous Nephropathy

Membranous nephropathy, often referred to as MN, is a type of kidney disease that is quite common, especially in adults. It’s the second most frequently occurring kidney disorder after a condition known as focal segmental glomerulosclerosis, or FSGS. In fact, among white adults, MN is the leading cause of a condition called primary nephrotic syndrome.

MN usually occurs in people over the age of 40, with the highest rates of the disease found in those aged 50 to 60 in the United States.
It’s more common in males, but females who have the disease generally have better outcomes.
Globally, the incidence of MN is 8 to 10 cases for every 1 million people. In the United States, it’s slightly higher at 12 cases per 1 million people every year.
While MN is less common in children, when it does occur, it is primarily caused by secondary factors.
MN may also coexist with other types of kidney disease, such as IgA nephropathy, FSGS, and lupus nephritis.

Signs and Symptoms of Membranous Nephropathy

When evaluating a patient, a thorough medical history and a full examination are often needed. This can include previous medical history, any medications or remedies being taken, family histories, any recent travel, allergies and social history – this information can suggest potential diagnosis. Membranous nephropathy (MN), for example, often shows up with symptoms similar to a condition called nephrotic syndrome, which can include weight gain, swelling all over the body, high blood pressure not responding to treatment, and foamy urine.

Patients with MN might also have signs of being more prone to blood clotting, due to losing an important anti-clotting substance called antithrombin 3 in their urine. These signs could include shortness of breath (which could be due to a pulmonary embolism, a blood clot in the lung), pain in the side along with blood in urine (suggesting renal vein thrombosis, a type of blood clot in the kidney), or pain in the calf (which could be a sign of deep vein thrombosis, a blood clot in the leg). Some patients might also have symptoms of heart failure.

Other ways MN might present include acute kidney injury, which could mean decreased urine production, frothy urine, and urinary tract infections. During a physical exam, the doctor might note high blood pressure, fluid buildup in the lower legs (referred to as “pitting pedal edema”), and severe whole body swelling called “anasarca”. Other signs could be crackling sounds in the lungs that suggest fluid buildup, and fluid in the abdominal cavity, known as “ascites”.

If the MN is secondary, which means it is caused by another disease or condition, the history and findings related to that primary condition should also be assessed. For example, in the case of lupus, rashes and joint pain might be present.

Coverage of medical history
Possible signs and symptoms
Information regarding current medication, travel, and family history
Check for key symptoms of nephrotic syndrome including weight gain, whole-body swelling, high blood pressure, and frothy urine
Monitoring for symptoms of blood clots such as shortness of breath, pain in the side, or pain in the calf
Observations of signs of heart failure
Evaluation of potential acute kidney injury evident by decreased urine, frothy urine, and urinary tract infections
Physical examination indicating high blood pressure, lower-leg fluid build-up, and whole-body swelling
Evaluation of any other symptoms correlated with the primary disease

Testing for Membranous Nephropathy

Your doctor may request a few routine lab tests to understand your condition more accurately. These may include blood tests to check levels of substances like creatinine, uric acid, vitamin D, and others. These tests help examine how well your kidneys are functioning.

Other tests may be conducted to assess protein levels in your blood, to see if they are lower than expected, which can be a sign of the disease. The doctor may also check for particular antibodies in the blood, specifically ones that can point to a specific type of kidney disease. If your medical history or symptoms suggest it, the doctor may order additional specific tests – for example to look for signs of infectious diseases or harmful substances in your blood.

A urine test is also typically performed. In this test, the doctor will be looking for proteins, blood cells, and other substances that should not be present in the urine. Sometimes, the doctor may also want to measure the amounts of certain substances in the urine over a 24-hour period, although this is not always necessary.

Imaging tests, such as an ultrasound, can be useful to look directly at the kidneys for any changes or abnormalities. If needed, other imaging tests may be used, such as a CT scan or an angiography, to check for issues like blood clots. However, it’s important to keep in mind that these tests involve the use of a contrast dye that could affect your kidneys, so your doctor will weigh the benefits and risks before deciding to use them.

If there are still uncertainties about your condition, your doctor might suggest a kidney biopsy. This test involves taking a small sample of kidney tissue to look at under a microscope. This can provide valuable information about the type and severity of kidney disease, and can help your doctor to make the most effective treatment plan for you.

Treatment Options for Membranous Nephropathy

The initial general management of your disease typically involves symptom relief. This can include medicines to remove excess fluids (diuretics), lower cholesterol (statins), control blood pressure (angiotensin-converting enzyme inhibitors or angiotensin receptor blockers), thin blood (anticoagulants), dietary salt restrictions, and other medicines to lower blood pressure. Around one-third of patients respond to these treatments, another one-third might need additional therapies.

One particular treatment option is immunosuppressive therapy, a type of treatment that decreases the body’s immune response. This helps prevent the immune system from attacking its own body tissues. For this, one regimen is the Ponticelli regimen that includes the administration of medications named methylprednisolone and prednisolone or prednisone, along with another medication called cyclophosphamide.

A modified version of the Ponticelli regimen may be given that involves changes in administered medications. Other than these standard meds, patients may also be given trimethoprim-sulfamethoxazole and valganciclovir to protect against pneumonia and viral infections.

A medication named Rituximab can be used as a second-line therapy after any failure of steroids. This drug can be administered as either a first-line therapy in hard-to-manage cases or after 6 months of the above treatment approaches.

Other treatment options include drugs like calcineurin inhibitors, which are not often used due to high instances of disease recurrence. Alternatives can be Tacrolimus or Cyclosporine in combination with prednisone. Some other drug options include Chlorambucil, Mycophenolate mofetil, and adrenocorticotropic hormone analogs.

Keep in mind, these treatments can have side effects, increasing the risk of infections, developing cancers, low blood counts, as well as long-term effects of steroids like cataract, metabolic syndrome, and damage to the joints.

If the disease is a result of another underlying condition, treating that particular cause is essential.

In case of severe kidney injury, renal replacement therapy, which mechanically filters the blood just like healthy kidneys, might be needed. Patients may also need supplementation of vitamin D and calcium, especially those being treated with steroids. In extremely severe cases with advanced kidney disease or end-stage kidney disease, a kidney transplant might be necessary.

Membranous nephropathy, or MN for short, is a kidney condition that needs to be distinguished from other similar conditions, all of which could cause a lot of protein to show up in a patient’s urine. There are a number of conditions that are similar enough to MN that they could be mixed up with it, mainly:

Focal Segmental Glomerulosclerosis, a disease that causes damage to kidney filters
Minimal Change Disease, a form of kidney disease that can cause suddenly occurring swelling
Diabetic Nephropathy, a serious kidney-related complication of type 1 diabetes and type 2 diabetes
IgA Nephropathy, also known as Berger’s disease, a kidney disease that occurs when an antibody abnormally deposits in the kidneys
Membranoproliferative Glomerulonephritis, a disorder that results in changes and inflammation in the kidneys

What to expect with Membranous Nephropathy

Let’s break down medical jargon for kidney disease and its treatment pattern. Complete remission means your proteinuria, that is the presence of excess proteins in your urine, is less than 0.3 grams per day (g/d) or 300 mg/g based on a spot urinary protein to creatinine ratio (UPCR) test. The UPCR test is like a snapshot of how your kidneys are functioning at that moment.

Partial remission signifies a reduction of proteinuria by more than 50% from the baseline. Also, when proteinuria is ranging between 0.3 to 3.5 g/d while the estimate Glomerular Filtration Rate (eGFR), a test that checks how well your kidneys are processing waste, remains relatively stable.

Relapse represents recurrence of proteinuria greater than 3.5 g/d after your symptoms had previously resolved. And End-Stage Kidney Disease (ESKD) is having a Glomerular Filtration Rate (GFR) of less than 15 ml per minute or when there’s a need for dialysis or a kidney transplant.

The ‘Rule of One-thirds’ reveals that a third of patients experience spontaneous remission with only conservative management. Another third have proteinuria symptoms without progressing into kidney failure and might benefit from therapies aimed at suppressing the immune system. However, the remaining third are resistant to treatment and need dialysis due to ESKD. Such patients should be evaluated for a possible kidney transplant.

There are risk factors linked to a poorer prognosis. These include being male or white, older age, presentation of hypertension, substantial proteinuria (more than 8 g/day) lasting for six months, high creatinine levels (a chemical waste molecule that is generated from muscle metabolism) or sudden kidney injury at the time of presentation, and extensive tubulointerstitial fibrosis (a pattern of chronic injury in the kidneys) as indicated by a biopsy.

Possible Complications When Diagnosed with Membranous Nephropathy

Complications can occur with certain medical conditions and treatments:

1. Complications from a blood clot in the lung, deep vein in the leg, kidney vein, and other blood clot-related incidents, as well as a higher risk of bleeding from widespread blood thinning therapy.

2. A kidney condition known as membranous nephropathy (MN) can lead to high cholesterol, high blood pressure, and chronic kidney disease, which could harm your heart health.

3. Furthermore, membranous nephropathy might evolve into chronic kidney disease, leading to lower than normal rates of kidney filtration. This could cause other health problems like anemia, disorders related to bone minerals and a deficiency in Vitamin D.

4. The following may result from immunotherapy complications and side effects:

An increased risk of infections like fungal, viral, and bacterial infections
An increased likelihood of developing cancers, such as bladder cancer, especially when using cyclophosphamide
Kidney damage and stones due to chemotherapy
Reduction in blood cells due to suppression of bone marrow
Risk of infertility with cyclophosphamide
Mycophenolate mofetil: May cause stomach issues, blood cell reduction, birth defects, hence requiring dual birth control methods during therapy
Become susceptible flare-ups of infections like tuberculosis and hepatitis B with rituximab
Infusion hypersensitivity reactions
Calcineurin inhibitors associated with kidney toxicity and nerve damage, induration of renal tissue, hair loss, and pancreas toxicity
Steroids enhancing the risk of infections, bone diseases like avascular necrosis of large joints, metabolic syndrome, salt and fluid retention causing high blood pressure, psychosis, and irritation in the stomach

5. Patients may enter the final-phase kidney disease stage, necessitating kidney replacement therapies with potential inherent complications.

6. Risks may involve bacteremia related to catheter use, low blood pressure, neurological side effects, and accelerated heart disease and death risks.

7. Recurrence of MN after a kidney transplant:

30% to 50% of patients with positive anti-PLA2R antibodies at the start show recurrence
The cause of recurrent MN is different from the initial MN

Preventing Membranous Nephropathy

It’s important for patients to understand that membranous nephropathy, a type of kidney disease, can be long-lasting and unpredictable. Being well-informed and following the treatment plan is key to managing this condition effectively. Special care and attention are given to patients who are in high-risk groups.

Those who are taking medications to suppress the immune system, a treatment for this disease, should be aware that they could have a higher chance of getting infections and other complications due to their suppressed immunity.

At every doctor’s appointment, it’s important to discuss the patient’s clinical status and the progress of their immune response. Regular blood tests and long-term monitoring are absolutely necessary. Some patients may experience advanced and persistent kidney problems that don’t respond well to treatment or were recognized late. For those individuals, treatments like hemodialysis or peritoneal dialysis – procedures to clean the blood when the kidneys can’t – might be required.

Patients should be thoroughly educated about these procedures and possible complications. If required, it may also be appropriate to discuss the option of a kidney transplant, including the option of receiving a kidney from a living donor. It’s also necessary to inform patients who receive a kidney transplant that the disease might come back even after the transplant.

Frequently asked questions

Membranous nephropathy is a type of kidney disorder that causes nephrotic syndrome, characterized by symptoms such as swelling in the arms and legs, high blood pressure, frothy urine, and signs of blood clots. It is caused by injury to specific cells in the kidney and the loss of a protective barrier, resulting in the loss of protein in the urine. Unlike other kidney conditions, it does not involve blood or blood cell fragments in the urine.

Globally, the incidence of MN is 8 to 10 cases for every 1 million people. In the United States, it's slightly higher at 12 cases per 1 million people every year.

Signs and symptoms of Membranous Nephropathy (MN) can include: - Weight gain - Swelling all over the body - High blood pressure not responding to treatment - Foamy urine - Signs of being more prone to blood clotting, such as: - Shortness of breath (which could indicate a pulmonary embolism) - Pain in the side along with blood in urine (suggesting renal vein thrombosis) - Pain in the calf (which could be a sign of deep vein thrombosis) - Symptoms of heart failure - Acute kidney injury, which may manifest as: - Decreased urine production - Frothy urine - Urinary tract infections - Physical exam findings may include: - High blood pressure - Fluid buildup in the lower legs (pitting pedal edema) - Severe whole-body swelling (anasarca) - Crackling sounds in the lungs suggesting fluid buildup - Fluid in the abdominal cavity (ascites) - If MN is secondary, symptoms related to the primary condition should also be assessed, such as rashes and joint pain in the case of lupus.

Membranous nephropathy can be acquired through primary factors, such as antibodies targeting specific proteins, or secondary factors, which include various diseases, infections, medications, exposure to heavy metals, autoimmune diseases, and other miscellaneous reasons.

Focal Segmental Glomerulosclerosis, Minimal Change Disease, Diabetic Nephropathy, IgA Nephropathy, Membranoproliferative Glomerulonephritis

To properly diagnose Membranous Nephropathy, a doctor may order the following tests: - Blood tests to check levels of substances like creatinine, uric acid, vitamin D, and others, to examine kidney function. - Tests to assess protein levels in the blood and check for specific antibodies that can indicate kidney disease. - Urine tests to look for proteins, blood cells, and other substances that should not be present, and possibly measure the amounts of certain substances over a 24-hour period. - Imaging tests, such as an ultrasound or CT scan, to directly examine the kidneys for abnormalities. - In some cases, a kidney biopsy may be necessary to obtain a small sample of kidney tissue for further examination.

The treatment options for Membranous Nephropathy include symptom relief through medications such as diuretics, statins, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, anticoagulants, and dietary salt restrictions. Immunossupressive therapy, such as the Ponticelli regimen, which includes medications like methylprednisolone, prednisolone or prednisone, and cyclophosphamide, may also be used. Other treatment options include medications like Rituximab, calcineurin inhibitors, Tacrolimus, Cyclosporine, Chlorambucil, Mycophenolate mofetil, and adrenocorticotropic hormone analogs. It is important to note that these treatments can have side effects and treating the underlying cause of the disease is essential. In severe cases, renal replacement therapy or kidney transplant might be necessary.

The side effects when treating Membranous Nephropathy can include: - Increased risk of infections like fungal, viral, and bacterial infections - Increased likelihood of developing cancers, such as bladder cancer, especially when using cyclophosphamide - Kidney damage and stones due to chemotherapy - Reduction in blood cells due to suppression of bone marrow - Risk of infertility with cyclophosphamide - Stomach issues, blood cell reduction, and birth defects with Mycophenolate mofetil, requiring dual birth control methods during therapy - Susceptibility to flare-ups of infections like tuberculosis and hepatitis B with rituximab - Infusion hypersensitivity reactions - Calcineurin inhibitors associated with kidney toxicity and nerve damage, induration of renal tissue, hair loss, and pancreas toxicity - Steroids enhancing the risk of infections, bone diseases like avascular necrosis of large joints, metabolic syndrome, salt and fluid retention causing high blood pressure, psychosis, and irritation in the stomach

The prognosis for Membranous Nephropathy can vary depending on individual factors, but there are generally three possible outcomes: 1. Complete remission: Proteinuria is less than 0.3 grams per day (g/d) or 300 mg/g based on a spot urinary protein to creatinine ratio (UPCR) test. 2. Partial remission: Proteinuria is reduced by more than 50% from the baseline, with proteinuria ranging between 0.3 to 3.5 g/d while the estimate Glomerular Filtration Rate (eGFR) remains relatively stable. 3. End-Stage Kidney Disease (ESKD): Glomerular Filtration Rate (GFR) is less than 15 ml per minute, requiring dialysis or a kidney transplant.

You should see a nephrologist for Membranous Nephropathy.