What is IgA Nephropathy (Berger Disease)?
Immunoglobulin A (IgA) nephropathy, also referred to as IgAN, is a leading cause of kidney disease and failure. The condition happens when IgA, a type of protein that helps your body fight infections (an antibody), is deposited in a part of the kidneys called the glomerular mesangium. This causes a harmful reaction from the immune system, damaging the basement membrane in the kidneys and leading to blood in the urine (hematuria), excessive protein in the urine (proteinuria), and reduced kidney function (renal insufficiency).
This condition was first defined by Berger and Hinglais back in 1968, and is sometimes referred to as Berger disease. When a biopsy is performed on the kidney, various types of damage may be visible, but the most common finding is growth of the mesangial cells within the kidney (mesangial proliferation) combined with a noticeable buildup of IgA.
In recent years, collaboration between scientists globally has helped us better understand the causes of IgAN, leading to new discoveries. The creation of research networks has also enabled the design and delivery of large studies, providing important insights into treatments aimed at controlling the immune response in this disease (immunotherapy).
The course of IgAN typically progresses slowly, but it’s important to note that between 20% and 50% of patients with this condition develop end-stage kidney disease (when kidneys can no longer function on their own) within 20 years. The rate of occurrence and severity of this condition vary widely, influenced by factors like ethnicity, race, geography, and genetics. For example, it’s observed that these problems are more common and serious in Asian populations.
What Causes IgA Nephropathy (Berger Disease)?
IgA Nephropathy (IgAN) happens when there are some issues with the immune system, causing a substance known as IgA to deposit in parts of the kidneys—this can lead to damage and scarring in these areas. It’s usually sparked by an infectious disease, which kicks off an overreaction of the immune system. However, the disease itself is not infectious, and there’s no evidence to suggest it’s caused by any particular germ or virus. Instead, it seems that various medical and genetic factors can trigger the immune system to respond this way.
In some cases IgAN might be linked to family history, but this is true for fewer than 10% of patients. Researchers have identified at least 18 different gene segments that, when altered, could play a role in IgAN. Two of these genetic segments include the C1GALT1 gene and the C1GALT1C1 gene.
IgAN is most commonly random, or idiopathic, meaning its cause is unknown. Over 90% of all cases fall into this category. There’s no evidence that suggests it’s caused by a specific infection, or by an allergic reaction to food, aside from a small group of patients with celiac disease. A theory suggests that this condition might be related to an abnormal process known as O-glycosylation, which promotes the formation of complex structures that contain IgA and other immune substances.
There are also quite a few systemic conditions that can lead to secondary IgAN. This includes liver, gastrointestinal, autoimmune, and dermatological disorders, along with infections, and drugs. It’s always important to determine if IgAN is primary or secondary, because secondary forms don’t typically require treatment with drugs that suppress the immune system. Rather, the focus would be on treating the underlying cause.
Another crucial factor to consider is the role of mucosal-associated lymphoid tissue (MALT)—tissue responsible for defending the body against environmental toxins and microbes. It’s largely found in the gut and tonsils, both of which have been linked to the development of IgAN.
Certain gastrointestinal disorders can trigger IgAN. In the case of liver disease, the organ is responsible for clearing large complexes of IgA molecules, and when the liver is compromised, this process doesn’t work as well. In rare cases, other liver disorders such as hemochromatosis, Wilson disease, and autoimmune hepatitis have been linked to IgAN.
Celiac disease, a disease where you cannot tolerate gluten, is closely related to IgAN. In patients with celiac disease, an enzyme can activate the production of IgG and IgA autoantibodies leading to IgAN.
Patients who have inflammatory bowel diseases like Crohn disease and ulcerative colitis also face a higher risk of developing IgAN, and can have increased mortality rates.
Autoimmune disorders, allergic skin conditions, and infections—especially those of the upper respiratory tract—all seem to carry a higher risk of developing IgAN. The link between an upper respiratory tract infection and visible blood in the urine is so common it has even been given its own term—synpharyngitic hematuria.
Lastly, medications such as tumor necrosis factor-α (TNF-α) inhibitors, have been associated with IgAN due to their effects on the body’s immune response. Other medications including interleukins 12 and 23 inhibitors, immune checkpoint inhibitors, oral anticoagulants, warfarin, and thioureylene derivatives also factor into the development of IgAN.
Understanding the cause or triggers of IgAN helps doctors determine the best treatment options. Treating the underlying causes can often help manage the symptoms of the disease.
Risk Factors and Frequency for IgA Nephropathy (Berger Disease)
IgAN, or IgA nephropathy, is a kidney disease that’s the leading cause of an inflammation condition called glomerulonephritis. However, it’s tricky to figure out how common this disease is because many people don’t show symptoms and the only sure way to diagnose it is through a kidney biopsy. There are people with IgAN who don’t get a biopsy and choose a less aggressive treatment, especially if their case doesn’t appear to be severe. In the United States, about 10% of kidney biopsies reveal IgAN, but it’s even more common in East Asia (found in up to 40% of biopsies) and Europe (found in 20% to 30% of biopsies). Overall, more than 2.5 out of every 100,000 people get diagnosed with IgAN based on biopsy studies from various countries.
There seems to be an early detection of the disease in East Asian kids due to routine urinalysis in schools. There’s also data showing a high burden of IgAN in Pacific and East Asian countries, which aligns with findings of a higher genetic susceptibility in these regions based on global genetic studies. Interestingly, East Asian patients with IgAN are more likely to develop end-stage kidney disease than non-Asian patients.
In the United States, White populations are more affected by IgAN than Black people. The disease mainly presents in children and young adults, with the most cases seen in people’s twenties and thirties. Men have a higher chance of getting IgAN than women in the United States and Europe, with a ratio of 2.5:1. In East Asia, this ratio is equal for men and women.
- IgAN is a kidney disease that’s the leading cause of a specific inflammation condition in the kidney.
- Many people with IgAN don’t show symptoms and a kidney biopsy is necessary for a definitive diagnosis.
- About 10% of kidney biopsies in the United States, up to 40% in East Asia, and 20% to 30% in Europe reveal IgAN.
- More than 2.5 out of every 100,000 people get diagnosed with the disease.
- Regular urine check-ups in East Asian schools lead to early disease detection.
- There’s a high genetic susceptibility to the disease in East and Pacific Asian countries.
- End-stage kidney disease is more common among East Asian patients with IgAN than non-Asian patients.
- In the United States, White populations are more affected by IgAN than Black populations.
- The disease mainly affects children and young adults, with a peak in people’s twenties and thirties.
- Men are more likely to have IgAN than women in the United States and Europe, but in East Asia, the disease affects both genders equally.
Signs and Symptoms of IgA Nephropathy (Berger Disease)
IgA Nephropathy (IgAN) usually shows no noticeable symptoms or physical signs. However, patients often report seeing gross hematuria, or blood in their urine, which can appear brown, red, or “coca-cola” colored. Severe kidney damage may lead to swelling in the ankles, a “puffy” face, and high blood pressure. Other potential symptoms include frothy urine or a skin rash. Patients commonly report recent upper respiratory infections, such as a sore throat, prior to the appearance of blood in their urine. Some patients may also experience hematuria after intense exercise. Insight into a patient’s history can be immensely helpful, particularly if previous urinalysis results are available.
During a physical exam, it’s important to measure blood pressure and look for signs of decreased kidney function like swelling, fluid in the abdomen, or unusual lung sounds. High blood pressure is common in people with IgAN, and the condition can often occur alongside cirrhosis, liver diseases, and celiac disease. Therefore, a thorough general and abdominal examination can help rule out these significant related conditions. The symptoms of IgAN can vary depending on the severity, ranging from undetectable hematuria to rapidly worsening kidney inflammation. The way symptoms present can also change based on a patient’s age and kidney biopsy results. The most common symptom pattern includes undetectable bloody urine and gradually worsening kidney disease.
Silent or asymptomatic hematuria with a small amount of protein in the urine (about 0.5 g/d) might be picked up during a routine screening. A small number of individuals presenting with undetectable bloody urine and small amounts of protein in the urine could eventually develop noticeable protein in the urine and high blood pressure, this really shows the importance of regular monitoring. Chronic kidney disease (CKD) is often observed in various groups. The survival rates for kidney health can greatly fluctuate based on things like when the biopsy was done and if there was lead-time bias. The estimated kidney survival rate 10 years after diagnosis varies between 57% and 91%.
Macroscopic hematuria appearing at the same time as a throat infection is often the first sign of IgAN; this leads to patients seeking medical help due to the simultaneous occurrence of noticeable hematuria and throat infection. Recurrence of macroscopic hematuria is also common. While high levels of protein in the urine can happen in IgAN, it is rare for both this and IgAN to occur at the same time.
Extrarenal (outside the kidney) symptoms of IgAN are not surprising given the systemic nature of the disease. Research has shown that up to 35% of patients experience gastrointestinal symptoms, including abdominal pain, cramps, and diarrhea.
Less than 5% of patients with IgAN present with acute kidney injury, which often results from rapid kidney structure damage or blockage due to gross hematuria and red blood cell casts. Though aggressive immune-system suppressing treatment is often necessary when the kidney structure changes, damage from a large amount of red blood cells can mostly be reversed with supportive treatment.
Testing for IgA Nephropathy (Berger Disease)
When your doctor suspects you might have IgA nephropathy, a kidney condition, several steps are taken to confirm the diagnosis. The initial test is a urine analysis to detect microscopic blood in your urine. High protein levels or the presence of red blood cells in your urine may indicate that your kidneys might be damaged.
Your doctor will also check your blood for a substance called creatinine, which is a waste product that healthy kidneys can filter out. Your estimated Glomerular Filtration Rate (GFR), which tells your doctor how well your kidneys are filtering your blood, is also calculated using the results of your creatinine test.
A confirmation of the diagnosis usually requires a kidney biopsy. The biopsy is a procedure where a tiny piece of your kidney is removed and examined under a microscope. This test can show whether there is a deposit of a protein called IgA in your kidney, which is considered the definitive sign of this disease.
Once the diagnosis of IgA nephropathy is confirmed, a tool known as the Oxford classification is used to predict how the disease might progress. It looks at various factors in your biopsy sample like the number of mesangial cells (cells in the kidney that help to regulate blood flow), endocapillary proliferation (increase of cells inside tiny blood vessels in the kidney), the presence of segmental glomerulosclerosis (a type of kidney damage), and signs of tubular atrophy or interstitial fibrosis (scarring within the kidney).
Certain markers, such as FSP1 and URG11, can also give valuable insights into the severity and potential progression of the disease. The presence of crescents, areas of severe inflammation and scarring in the kidneys, is still a matter of debate and is generally not used as a factor in disease prognosis.
Other possible signs of IgA nephropathy include special tests on urine samples that look for proteins related to the immune response. Although, tests measuring the levels of galactose-deficient IgA are sometimes used, they should be interpreted carefully as even some healthy relatives of IgA nephropathy patients can have elevated levels of this protein.
In summary, the diagnosis and prognosis of IgA nephropathy involves a series of lab tests, urine analysis, and biopsy. This comprehensive approach helps your doctor make an accurate diagnosis and map out an effective treatment plan for you.
Treatment Options for IgA Nephropathy (Berger Disease)
IgA Nephropathy (IgAN), often diagnosed through a kidney biopsy, begins with ruling out other causes and assessing various factors such as protein levels in urine, kidney function, blood pressure, and how the disease looks under the microscope. The main goals of treatment are to control the disease and prevent complications.
The first line of treatment usually involves medication to control protein levels in the urine and lower blood pressure. The chosen drugs are typically either angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs). The goal is to maintain your blood pressure under 130/80 mm Hg. If your protein levels in urine exceed 1 g/d, the goal is to keep your systolic blood pressure (the top number) under 125 mm Hg.
Conservative therapy can reduce protein levels in the urine and slow the rate at which kidney function declines in patients with IgAN. Some patients can achieve satisfactory results without the need for immune system-suppressing therapies, by optimizing conservative measures such as aggressive use of ACE inhibitors or ARBs.
The role of ACE inhibitors or ARBs in IgAN is well established, but caution is needed as these can cause high potassium levels in the blood. In addition, an individual lifestyle changes should be made, including quitting smoking, reducing salt intake, managing lipid levels, losing weight, and quitting smoking. Smoking has been shown to worsen IgAN, especially as kidney function declines.
Corticosteroids are sometimes used to lower protein levels in urine, especially when levels are very high. A tapered course of prednisone is usually prescribed for 2 to 4 months.
New treatments have come onto the scene in recent years, such as sparsentan, a novel drug that acts on the endothelin and angiotensin receptors and has shown promising results. Other emerging treatments include a specially formulated version of budesonide that releases the drug in a specific area of the intestine where IgA is produced, and newer drugs that affect glucose and sodium levels in the kidneys.
Other treatments that suppress the immune system have also been studied, including mycophenolate mofetil and rituximab, among others. However, their effectiveness in treating IgAN is currently unclear.
Sometimes, a combination of corticosteroids with other drugs is used for progressive cases of IgAN. Results have varied.
The role of tonsillectomy, or removal of the tonsils, in treating IgAN is still debated. It’s thought that removing the tonsils decreases IgA levels. Some studies, especially in Asian populations, have shown benefits. However, this procedure is not commonly included in standard care guidelines worldwide.
If IgAN progresses to end-stage renal disease, kidney transplantation could be considered, although there’s a risk that IgAN will recur in the transplanted kidney. To mitigate this risk, specialists could consider different approaches like maintaining immunosuppression with corticosteroids and using ACE inhibitors or ARBs.
Various potential treatments targeting different aspects of IgAN are currently in development. These new treatments being studied include drugs that modulate blood pressure, drugs that inhibit the action of B cells (which produce the abnormal IgA1 molecules in IgAN), and drugs that inhibit parts of the immune system’s complement system that contribute to IgAN. More research and development are necessary, but it’s a promising area for future treatment options.
What else can IgA Nephropathy (Berger Disease) be?
There are two conditions with symptoms that can be mistaken for IgA nephropathy, or IgAN, which are:
- IgA Vasculitis – Also known as Henoch-Schönlein purpura, this condition has similar symptoms to IgAN due to improper IgA deposits that mainly affect the small blood vessels of oppressed organs. One key difference is that IgA Vasculitis commonly affects those aged 15 and under, while IgAN typically targets people aged 15 and above. The damage seen under a microscope is different too; IgA vasculitis tends to cause more harm to the capillaries and glomerulus (a part of the kidney), whereas, in IgAN, the kidney issue known as mesangial proliferation is more common. Interestingly, both diseases share some treatment protocols due to their autoimmune nature. For further details, you can reference the article “IgA Vasculitis (Henoch-Schönlein Purpura)” on the StatPearls website.
- Poststreptococcal Glomerulonephritis – This condition usually appears 2 to 3 weeks after having an upper respiratory infection, unlike IgAN which often manifests alongside or shortly after the infection. For further information, refer to the StatPearls article titled “Poststreptococcal Glomerulonephritis”.
Other potential ailments that medical staff might consider while diagnosing IgAN include:
- Lupus nephritis, which is diagnosed if multiple bodily systems are affected.
- Membranoproliferative glomerulonephritis, recognized by a kidney biopsy.
- Thin basement membrane nephropathy, which typically presents with unnoticeable blood in urine and a history of harmless blood in urine in the family.
- Alport syndrome, known by its eye and ear symptoms.
- Different cancers from the kidneys to the urethra (all patients over the age of 40 should be cleared for this).
- Urolithiasis (kidney stones), which usually arise with a certain type of pain not related to IgAN; obstructing stones can be found via imaging techniques.
What to expect with IgA Nephropathy (Berger Disease)
About half of the patients with a condition called IgAN (IgA Nephropathy) experience a course of the disease that is relatively harmless. The future progression of this disease can be estimated with the help of a classification system known as the Oxford classification.
Four factors from the Oxford classification (the MEST criteria) and an additional factor called crescents, are associated with a poor outcome. However, if the patient only has minor symptoms such as microscopic blood in their urine (hematuria) and mild protein loss in urine (proteinuria), this usually points to a more harmless and symptom-free disease progression.
People of East Asian heritage have a higher risk of developing ESRD (End-Stage Renal Disease) when suffering from this disease. Three risk factors that are strongly tied to ending up needing dialysis or even facing death are:
* Protein loss in urine of 1 gram per day or more
* Constant high blood pressure
* High Oxford classification MEST-C score (some doctors also consider crescents).
People with constant proteinuria of 1 gram per day or more have a significantly increased risk, 46 times higher, of developing ESRD as compared to those having less than 500 milligrams per day. With appropriate treatment, about half of the patients may obtain a complete remission, whereas the remaining may experience ongoing symptoms or complications.
The MEST-C score is assigned based on certain physical changes that are observed in the small filtering units in your kidneys (glomeruli) and surrounding kidney tissue. These changes are seen under a microscope and include too many cells in certain areas (Mesangial and Endocapillary hypercellularity), scar tissue or hardening in certain parts of the glomeruli (Segmental glomerulosclerosis), wasting away and hardening of the tube that carries urine (Tubular atrophy) and the tissue around it (interstitial fibrosis), and excessive growth of cells outside the normal area (Cellular/fibrocellular crescents). A minimum of 8 healthy glomeruli are needed to calculate this score accurately.
Possible Complications When Diagnosed with IgA Nephropathy (Berger Disease)
Even though only a small number of patients with IgAN, a type of kidney disease, end up with ESRD (a condition where the kidneys stop working completely), it’s still a common cause of ESRD due to how many people have IgAN. As the disease gets worse, it can lead to health problems like high blood pressure, swelling, anemia, heart failure, and fluid in the lungs.
Both steroid treatments and alternatives to steroids can cause side effects and complications. These can include higher risk of infections, high blood pressure, fluid buildup, weight gain, diabetes, weakened bones, and a condition where the body has too much of the hormone cortisol. Treatments that avoid steroids can also cause immune system suppression, severe allergic reactions, kidney damage, and liver damage.
Common Side Effects:
- High blood pressure
- Swelling
- Anemia
- Heart failure
- Fluid in the lungs
- Increased risk of infections
- Fluid buildup
- Weight gain
- Diabetes
- Weakened bones
- Excessive cortisol in the body
- Suppressed immune system
- Severe allergic reactions
- Kidney damage
- Liver damage
Recovery from IgA Nephropathy (Berger Disease)
People with IgAN, a kidney condition, are often advised to follow a low-antigen diet. This means limiting intake of food elements that can provoke an immune response, such as gluten, meat, and dairy products. Some research supports the idea that eating less protein can help slow down the worsening of kidney function.
Preventing IgA Nephropathy (Berger Disease)
Educating patients and encouraging preventive behaviors are key to managing IgAN (a type of kidney disease), especially as this condition can be sparked by minor URIs (upper respiratory infections) in people who are genetically at risk.
A minor URI like a cold or the flu could trigger IgAN in patients who already have a genetic predisposition to the disease.
People with other autoimmune diseases and a strong family history of IgAN are more likely to develop this condition.
Regular screening for hematuria, or blood in the urine, is vitally important in catching the disease early. This allows doctors to identify patients who have the disease but are not showing symptoms yet.
Patients should receive detailed education about their condition. This includes understanding what the disease is, knowing that it might progress to ESRD (end-stage renal disease) which could require a kidney transplant, being aware of the possible side effects of steroid therapy, and recognizing the critical importance of having regular follow-up appointments with their healthcare provider.
Patients should be reminded of the importance of sticking to their prescribed medication routine, which could include drugs like ACE inhibitors or ARBs (both are medications to treat high blood pressure and kidney diseases).
Dietary recommendations for patients with IgAN often include reducing salt, protein, and saturated fat intake for better health management.
