What is Rapidly Progressive Glomerulonephritis?
Rapidly progressive glomerulonephritis (RPGN) is a condition that affects your kidneys. It’s known for three things:
- A quick decrease in kidney function over a short period of time (days to weeks)
- Signs of kidney damage in your urine—blood, unusual-looking red blood cells, red blood cell clumps, and excess protein
- Characteristic changes when a kidney tissue sample is examined under a microscope— the cells in a part of the kidney called glomeruli multiply and form a crescent shape. This is also known as crescentic glomerulonephritis.
Because the terms RPGN and crescentic glomerulonephritis describe the same kidney changes, they are often used interchangeably. More than half of the glomeruli should have these crescents for it to be named crescentic glomerulonephritis. But, even a single crescent can point to an underlying kidney disease. The earlier this condition is diagnosed and treated, the higher the chances of preventing more kidney damage.
RPGN is classified into types one, two, three and four based on the changes seen under the microscope and where immune complexes (proteins from your immune system) are deposited in the kidney:
- Type I: Anti-glomerular basement membrane (GBM) linear antibody deposition disease – antibodies stick to a specific part of the kidney.
- Type II: Granular immune complex deposition disorders – immune complexes are scattered through parts of the kidney.
- Type III: Pauci-immune disease (absence of deposition, generally associated with a type of inflammation called ANCA-positive vasculitis).
- Type IV: Double antibody positive for both ANCA and anti-GBM – antibodies linked with both conditions are present.
There are also some mixed types of RPGN that show features of two or more of these classifications.
What Causes Rapidly Progressive Glomerulonephritis?
Rapidly progressive glomerulonephritis (RPGN) is a kidney disease that can be categorized based on tissue analysis and immune complex deposition in three general ways:
1. Anti-Glomerular Basement Membrane Disease – This disease happens when the body forms antibodies against a specific protein found in the basement membrane of the kidney and lung cells. This accounts for 10% to 15% of RPGN cases. Around half of these cases also experience bleeding in the lungs, known as Goodpasture syndrome. Some people show mild kidney impairment, high-protein urine, and blood in the urine. Despite not having the typical symptoms of RPGN, they’re found to have this disease through a biopsy.
2. Granular Immune Complex Glomerulonephritis – This condition accounts for about 25% to 30% of RPGN cases. It’s more commonly found in adults, while children more often suffer from a related disease called immune complex RPGN. The most frequent causes for this in children are IgA nephropathy, lupus nephritis, cryoglobulinemia, IgA vasculitis, and postinfectious glomerulonephritis. This is more common in lower-income countries because of a higher prevalence of infectious diseases. It can also be caused by a vast variety of illnesses and conditions such as infections, lupus, certain types of vasculitis, and hepatitis.
3. Pauci-Immune Glomerulonephritis or Anti-Neutrophil Cytoplasmic Antibody–Associated Vasculitis – This condition accounts for 40% to 50% of adult RPGN cases and represents the most common form seen in adults. It typically falls into three subtypes, each with varying levels of kidney involvement.
In some rare cases, RPGN can be caused by certain medications. And in very few instances, some people can test positive for both ANCA and anti-GBM antibodies – a disease known as double-positive antibody disease. The presence of these antibodies impacts how the disease is treated.
Risk Factors and Frequency for Rapidly Progressive Glomerulonephritis
Rapidly progressive glomerulonephritis (RPGN) is a rare global health condition, with an occurrence of roughly 7 cases per 1 million people every year in the U.S. and 2 per 1 million in the U.K. The condition is reported more commonly in White and Asian communities than in Black communities. There’s no significant difference between the number of diagnosed men and women, as the ratio is roughly 1:1. Often, the condition will become apparent for the first time either around the age of 30 or later in a person’s late 60s, though cases have been observed in individuals from 2 to 92 years old. It is, however, rarely seen in children.
GBM disease makes up around 10% to 15% of all instances of diffuse crescentic glomerulonephritis. Annually, it affects around 0.5 to 0.9 people per million, with most sufferers being White. Like RPGN, the disease tends to become most apparent in patients around the age of 30, with slightly more men affected than women, or in patients in their sixties, with slightly more women affected than men.
- Pauci-immune RPGN is the most frequently seen variant of crescentic glomerulonephritis, comprising 40%-50% of the cases, and is predominantly found in White population.
- The peak age for the onset of this condition is 60 to 85 years, with the majority of patients testing positive for ANCA.
- RPGN seldom results in end-stage kidney disease.
- Interestingly, in the U.S. and Europe PR3-ANCA positivity is more prevalent, but in Japan, MPO-ANCA positivity is more common.
Signs and Symptoms of Rapidly Progressive Glomerulonephritis
A quick decrease in kidney function can happen within a few weeks to months, often characterized by early nonspecific symptoms. In some cases, coughing up blood and difficulty breathing may be the first apparent symptoms.
Anti-GBM disease can result in large-scale lung bleeding and kidney complications. The symptoms one might experience include difficulty breathing, coughing, coughing up blood, kidney inflammation, blood in urine, and swelling. People under the age of 30 usually experience more lung-related issues compared to older individuals.
Some symptoms hinting at immune complex disorders or ANCA vasculitis include:
- Systemic symptoms: Fevers, night sweats, weight loss, joint pain
- Mouth symptoms: Ulcers in the mouth
- Eye symptoms: Inflammation of the whites of the eyes
There could also be symptoms involving the ear, nose, and throat such as hearing loss, ear inflammation, nosebleeds, nasal drainage, sinus inflammation, and decay of the nasal cartilage. Respiratory symptoms might include difficulty breathing, coughing, hoarseness, and coughing up blood. Digestive symptoms could involve pain in the stomach due to inadequate blood supply, tissue death, or inflammation of the pancreas. Central nervous system signs might include vision changes such as blurred vision or vision loss, numb feeling, weakness, and stroke-like symptoms. Skin symptoms could involve a type of skin rash that feels rough, skin ulcers, and a mottled discoloration of the skin caused by small blood vessels below the surface.
If not treated quickly, progressive loss of kidney function could lead to kidney failure. Symptoms at this stage may include tiredness, loss of appetite, feeling sick, vomiting, and decreased urine output.
Some research suggests that in patients who test positive for both anti-GBM and ANCA antibodies, the kidney symptoms follow a pattern characteristic of anti-GBM disease, both clinically and under the microscope, whereas the extra-kidney symptoms are similar to those of ANCA-associated vasculitis.
Testing for Rapidly Progressive Glomerulonephritis
When your doctor suspects you could have Rapidly Progressive Glomerulonephritis (RPGN), a condition that causes rapid loss of kidney function, they will use several tests to confirm their diagnosis. Here’s what these tests might include and why they are essential:
Lab Tests:
Your doctor may ask for a urine analysis. If certain red blood cells (RBCs) are seen under the microscope, this could suggest a kidney problem. Also, if your urine protein-to-creatinine ratio is high, it may be a sign of a more advanced stage of disease. Your doctor may also order blood tests which would measure creatinine and electrolytes like potassium, magnesium, and calcium. Elevated levels might show that your kidneys are not working as they should be. Lastly, a complete blood count could show an increase in a type of white blood cell called eosinophils which is common in a certain type of vasculitis which might cause RPGN.
Some tests look for specific anti-GBM (glomerular basement membrane) antibodies in your blood. Although, absence of these antibodies does not necessarily rule out the disease as about 10% of patients with this disease would not have these antibodies identified using conventional testing methods.
Another testing method is ANCA testing (antineutrophil cytoplasmic antibodies), previously done using indirect immunofluorescence has now been replaced by a new method which not only identifies specific antigens but also provides more details about the levels of certain antibodies which can give additional clues towards the diagnosis.
Infections can sometimes cause RPGN, so your doctor might also check for infections like strep, HIV, Hepatitis B and C. Conditions like lupus, or primary membranoproliferative glomerulonephritis might cause this disease and in those cases, certain components in your blood called Complement C3 and C4 might be low. So, your doctor might check the levels for these as well.
Lastly, depending on the results of these tests, your doctor might check for a couple of recently identified antibodies which have been associated with certain types of this disease.
All in all, these tests are crucial in helping your doctor rule out other conditions and make an informed diagnosis.
Imaging and Diagnostic Tests:
Your doctor may order a chest x-ray or a CT scan to check for signs of lung bleeding or vasculitis (inflammation of blood vessels). If lung bleeding might be occurring a test called bronchoscopy might be performed. Also, further visual examinations might be done as well as skin biopsies. In the end, the most definitive method to diagnose RPGN is a kidney biopsy which can provide a detailed view of the changes occurring in your kidney.
Treatment Options for Rapidly Progressive Glomerulonephritis
Rapidly progressive glomerulonephritis (RPGN) is a severe kidney condition that can lead to loss of kidney function within weeks to months if not treated. That’s why beginning treatment as soon as possible is essential for preserving the health and function of the kidneys.
Many treatments for RPGN involve the use of immunosuppressive therapy, a type of therapy aimed at reducing the body’s immune response. Usual medications given include glucocorticoids, which are types of steroids that help reduce inflammation in the kidney and prevent further damage. Using these medications along with immunosuppressants has been found effective and reduces chances of the disease returning. Other medications that might be given include azathioprine, methotrexate, cyclosporine, and mycophenolate mofetil, depending on the clinician’s judgement and the patient’s condition.
However, there are situations where it may not be safe to use immunosuppressants, like if the patient has an active infection, low white blood cell count, or liver dysfunction. In these cases, a treatment called plasmapheresis, which involves removing and filtering the blood before returning it to the body, could be considered.
Sometimes treatment may be started before a definitive diagnosis is made. This includes giving a high dose of a glucocorticoid like methylprednisolone, either 500mg or 1g, for at least 3 doses. This treatment choice depends on the patient’s specific signs and symptoms, and the test results available at the time.
For a specific type of RPGN, known as anti-glomerular basement membrane disease, the preferred treatment is plasmapheresis in combination with immunosuppressive agents. This helps to remove harmful antibodies from the blood. Starting this treatment as early as possible is important to prevent further damage to the kidneys and lungs.
Lastly, the type of RPGN associated with neutrophil cytoplasmic antibodies (ANCA), which are proteins that can be found in the blood, is typically treated with an intravenous dose of methylprednisolone followed by oral prednisone, intravenous or oral cyclophosphamide or rituximab, and plasmapheresis. This is usually carried out over 3 to 4 months, followed by maintenance therapy.
A medication called rituximab, a type of drug that targets specific immune cells, may also be used because of its effectiveness in controlling the condition and preventing it from returning.
Remember, each patient’s situation and response to treatment is unique, so your healthcare provider will determine the most suitable course of action for you.
What else can Rapidly Progressive Glomerulonephritis be?
When a doctor is trying to diagnose RPGN, a type of kidney disease, they need to first rule out other conditions that might cause similar symptoms such as sudden loss of kidney function, presence of excess protein in urine, and presence of red blood cells in urine. These conditions could include:
- Kidney damage due to insufficient blood flow to the kidneys
- Kidney injury due to damage to the kidney cells that filter waste from blood
- Blockage of the urinary tract
- Nephrotic syndrome caused by various diseases damaging kidneys
- Blood in urine due to a problem in the urinary system
- A disorder causing blood clots to form in various organs
- Conditions causing the formation of small blood clots within the circulation
It’s crucial for the doctor to exclude these conditions by conducting appropriate investigations in order to reach an accurate diagnosis.
What to expect with Rapidly Progressive Glomerulonephritis
Rapidly progressive glomerulonephritis (RPGN), a severe kidney condition, requires immediate treatment to prevent irreversible damage. Age and gender don’t greatly impact the disease’s outcome, however, it’s noticed that children typically recover better than older adults. The level of protein in the urine (proteinuria) doesn’t impact the short-term outcome, yet if proteinuria persists despite treatment, it suggests poor long-term outcomes.
The kidney function at the start of treatment can show how severe the disease is, with factors like high serum creatinine level (a waste product measured in blood tests), the absence of urine output (anuria), or the need for dialysis often linked to a poorer outcome and progression to kidney failure.
The extent of damage seen microscopically can indicate the prognosis. For example, if over half of the kidney’s filtering units (glomeruli) are undamaged, the odds of the kidney recovering are above 90%, 5 years after treatment. Conversely, if more than half are severely scarred (globally sclerosed), the 5-year recovery rate drops below 25%.
Antibody levels (the body’s immune response) before treatment also influence the outcome. High anti-GBM antibodies denote a worse kidney outcome, while ANCA antibodies that don’t reduce with treatment suggest a more severe form of disease. Relapse in anti-GBM disease is rare with less than 3% rate.
Without treatment, the most common form of RPGN in Western countries has an 80% mortality rate. However, with aggressive immunosuppressive treatment (that reduces the response of the immune system), survival rates increase to 75% after 5 years. Approximately 25% of patients progress to end-stage kidney disease, especially older patients, those on dialysis, or those with lung bleeding. Disease relapse occurs in about 40% of patients, hence, continuous monitoring is important.
In patients with ANCA-associated disease, mortality is often linked to lung involvement, especially in younger individuals. After immunosuppressive treatment, infection is the most common cause of death.
A specific complication, ‘crescentic glomerulonephritis’, can occur in a disease called IgA nephropathy. If ‘crescents’, a sign of bad damage, are seen in over 25% of glomeruli, the prognosis is usually worse and less likely to recover fully. Therefore, in IgA nephropathy disease, it’s crucial to look for crescents or other signs of autoimmunity.
Possible Complications When Diagnosed with Rapidly Progressive Glomerulonephritis
Complications from certain diseases and their treatments can really be split into two groups. The first group is complications that come directly from the illness itself.
Disease-Related Complications:
- Bleeding in the lungs, which is common in anti-GBM disease.
- In lupus-related RPGN, kidney disease caused by immune complex deposits can also result in symptoms outside the kidneys. For example, they can lead to serositis (inflammation of tissues lining the body cavities), cerebritis (inflammation of the brain), and skin issues. For more details about this, you can refer to StatPearls’ reference on “Lupus Nephritis.”
The second group is complications that result from the treatments used for the disease.
Treatment-Related Complications:
- Immunosuppressive therapy, a treatment which lowers the body’s immune response, can lead to various types of infections. These infections can sometimes even be life-threatening.
- Cyclophosphamide, a specific drug used in treatment, can have side effects like cystitis (bladder inflammation) and hematuria (blood in urine). Older patients are especially susceptible to these complications.
- Plasmapheresis, a procedure that filters the blood, is linked with the removal of blood clotting factors. This increases the patient’s risk of bleeding.
Preventing Rapidly Progressive Glomerulonephritis
Getting a quick diagnosis and starting treatment right away can make a big difference in how well people recover from a disease known as RPGN (Rapidly progressive glomerulonephritis), it affects the kidneys quickly. Those at high risk for this disease should be aware of symptoms that include producing less urine, seeing blood in their urine, difficulty breathing, coughing up blood, and other signs of overall body illness. If any of these symptoms arise, they should reach out to a healthcare professional right away.
All patients need to understand the importance of sticking with their treatment plan and knowing the potential side effects, in case they consider stopping their medication. They should reach out to a healthcare provider before deciding to stop taking a medication.
Patients also need to be aware of the possible serious side effects of drugs that suppress the immune system, including the risk of getting different infections and harmful effects on unborn babies. They should know about the importance of taking preventative antibiotics and getting the right vaccinations to prevent infections that take advantage of weakened immune systems.
