Overview of Glomerular Diseases
Many diseases affect kidney function by attacking the glomeruli, the tiny units within the kidney where blood is cleaned. Glomerular diseases include many conditions with a variety of genetic and environmental causes and have the potential to lead to kidney failure.
Glomerular diseases damage the glomeruli, letting protein and sometimes red blood cells leak into the urine. Sometimes a glomerular disease also interferes with the clearance of waste products by the kidney, so they begin to build up in the blood. Furthermore, loss of blood proteins like albumin in the urine can result in a fall in their level in the bloodstream. In normal blood, albumin acts like a sponge, drawing extra fluid from the body into the bloodstream, where it remains until the kidneys remove it. But when albumin leaks into the urine, the blood loses its capacity to absorb extra fluid from the body. Fluid can accumulate outside the circulatory system in the face, hands, feet, or ankles and cause swelling.
Patients with glomerular disease have significant amounts of protein in the urine, which may be referred to as “nephrotic range” if levels are very high. Red blood cells in the urine are a frequent finding as well, particularly in some forms of glomerular disease. Urinalysis provides information about kidney damage by indicating levels of protein and red blood cells in the urine. Blood tests measure the levels of waste products such as creatinine and urea nitrogen to determine whether the filtering capacity of the kidneys is impaired. If these lab tests indicate kidney damage, the doctor may recommend ultrasound or an X-ray to see whether the shape or size of the kidneys is abnormal. These tests are called renal imaging. But since glomerular disease causes problems at the cellular level, the doctor will probably also recommend a kidney biopsy—a procedure in which a needle is used to extract small pieces of tissue for examination with different types of microscopes, each of which shows a different aspect of the tissue. A biopsy may be helpful in confirming glomerular disease and identifying the cause.
A number of different diseases can result in glomerular disease. It may be the direct result of an infection or a drug toxic to the kidneys, or it may result from a disease that affects the entire body, like diabetes or lupus. Many different kinds of diseases can cause swelling or scarring of the nephron or glomerulus. Sometimes glomerular disease is idiopathic, meaning that it occurs without an apparent associated disease.
When the body’s immune system functions properly, it creates protein-like substances called antibodies and immunoglobulins to protect the body against invading organisms. In an autoimmune disease, the immune system creates autoantibodies, which are antibodies or immunoglobulins that attack the body itself. Autoimmune diseases may be systemic and affect many parts of the body, or they may affect only specific organs or regions.
Specific Glomerular Diseases
Systemic lupus erythematosus (SLE) affects many parts of the body: primarily the skin and joints, but also the kidneys. Because women are more likely to develop SLE than men, some researchers believe that a sex-linked genetic factor may play a part in making a person susceptible, although viral infection has also been implicated as a triggering factor. Lupus nephritis is the name given to the kidney disease caused by SLE, and it occurs when autoantibodies form or are deposited in the glomeruli, causing inflammation. Ultimately, the inflammation may create scars that keep the kidneys from functioning properly. Conventional treatment for lupus nephritis includes a combination of two drugs, cyclophosphamide, a cytotoxic agent that suppresses the immune system, and prednisone, a corticosteroid used to reduce inflammation. A newer immunosuppressant, mycophenolate mofetil (MMF), has been used instead of cyclophosphamide. Preliminary studies indicate that MMF may be as effective as cyclophosphamide and has milder side effects.
Anti-neutrophil Cytoplasmic Antibody (ANCA)-associated Glomerulonephritis
Antibodies to neutrophil (the most common white blood cell in our bodies) components are called ANCAs. They react with specific antigens in storage compartments (primary granules) in the cytoplasm of neutrophils. Glomerular diseases caused by ANCAs include Wegener’s granulomatosis, microscopic polyangiitis, and renal-limited vasculitis.
There are two main types of ANCAs, distinguished by their staining patterns. Cytoplasmic ANCA (cANCA) produces a cytoplasmic staining pattern with central accentuation in alcohol-fixed neutrophils. Perinuclear pattern ANCA (pANCA) demonstrates a perinuclear staining pattern of alcohol-fixed neutrophils, which is actually an artifact of the fixation process. ANCA specificity is determined by enzyme-linked immunosorbent assay (ELISA), with cANCA most commonly an antibody directed against proteinase 3 (PR3) and with pANCA most commonly an antibody directed against myeloperoxidase (MPO).
Nonspecific pANCA can occur in association with other autoimmune or inflammatory diseases, but they do not have the MPO specificity. The most common occurrence is in systemic lupus erythematosus. Other associated diseases include inflammatory bowel disease, sclerosing cholangitis, autoimmune hepatitis, rheumatoid arthritis, and Felty syndrome.
The link between ANCAs and the pathogenesis of ANCA-associated disease is unclear; however, it is believed that ANCAs can activate neutrophils, leading to tissue injury at the site of this activation such as in the glomerulus.
The ANCA-associated diseases are closely related and are distinguished by only a few clinical and pathologic criteria.
Wegener’s granulomatosis is characterized by the presence of upper and lower respiratory problems, including sinus inflammation and lung involvement (infiltrates on chest x-ray). Patients can present with sinusitis or coughing up blood. The kidneys are involved, sometimes with renal failure.
Of patients with Wegener’s granulomatosis, 80-90% have findings positive for ANCA and almost all have a cANCA (anti-PR3). A negative test result for ANCA does not exclude the presence of Wegener’s granulomatosis.
Microscopic polyangiitis is characterized by lung involvement (as shown by infiltrates on chest x-ray) and rapidly progressive glomerulonephritis, often coupled with abnormalities of the muscles or joints, and at times involvement of the nervous system, including peripheral nerve damage. The term polyangiitis is used in preference to arteritis because vessels other than arteries are normally involved in the disease.
Of patients with microscopic polyangiitis, 80-90% have positive findings for ANCA and almost all have a pANCA (anti-MPO). A negative test result for ANCA does not exclude the presence of microscopic polyangiitis. Isolated necrotizing crescentic glomerulonephritis is the renal-limited form of microscopic polyangiitis.
Membranous nephropathy is the second most common cause of the nephrotic syndrome (proteinuria, edema, high cholesterol) in U.S. adults after diabetic nephropathy. Diagnosis of membranous nephropathy requires a kidney biopsy, which reveals unusual deposits of immunoglobulin G and complement C3, substances created by the body’s immune system. Fully 75 percent of cases are idiopathic, which means that the cause of the disease is unknown. The remaining 25 percent of cases are the result of other diseases like systemic lupus erythematosus, hepatitis B or C infection, or some forms of cancer. Drug therapies involving penicillamine, gold, or captopril have also been associated with membranous nephropathy.
About 20 to 40 percent of patients with membranous nephropathy progress, usually over decades, to total kidney failure, but most patients experience either complete remission or continued symptoms without progressive kidney failure.
Doctors disagree about how aggressively to treat this condition, since about 20 percent of patients recover without treatment. Medications such as angiotensin-converting enzyme inhibitors (ACE inhibitors) or angiotensin receptor blockers (ARBs) are generally used to reduce proteinuria. Additional medication to control high blood pressure and edema is frequently required. Some patients benefit from steroids, but this treatment does not work for everyone. Additional immunosuppressive medications are helpful for some patients with progressive disease.
Membranoproliferative Glomerulonephritis (MPGN)
Membranoproliferative glomerulonephritis is a kidney disorder that involves inflammation and changes in the microscopic structure of kidney cells. It leads to disrupted kidney function.
MPGN is caused by an abnormal immune response. Deposits of antibodies build up in a part of the kidneys called the glomerular basement membrane. This membrane helps filter waste and extra fluid from the blood.
The changes in this membrane lead disrupt the body's ability to filter urine. Protein and fluid leak out of the blood vessels into body tissues, leading to swelling (edema). Nitrogen waste products may build up in the blood (azotemia) because of poor kidney functioning.
There are two forms of MPGN, which are called MPGN type I and MPGN type II. The latter is frequently also termed Dense Deposit Disease.
Most cases of MPGN are type I, with MPGN type II being much less common than MPGN type II. It also tends to get worse faster than MPGN type I.
The conditions affect both men and women, mostly under age 30. Symptoms can include: 1) Blood in the urine; 2) Dark urine (smoke, cola, or tea colored); 3) Cloudy urine; 4) Decrease in urine volume; 5) Swelling of any part of the body; and, 6) Changes in mental status such as decreased alertness or decreased concentration.
The results of a physical examination vary depending on the symptoms. Swelling may be present along with signs of fluid overload, such as abnormal sounds when listening to the heart and lungs with a stethoscope. Blood pressure is often high because of increased water and sodium (salt) retention and increased production of renin, a hormone that controls blood pressure.
MPGN may present in several forms. It may be seen as acute nephritic syndrome, nephrotic syndrome, or an abnormal urinalysis without symptoms.
Tests that can help confirm the diagnosis include: 1) Urinalysis; 2) Urine protein measurements; 3) measurements of BUN and creatinine in blood; and, 4) Measurements of components of the complement proteins in the blood. A kidney biopsy is necessary to confirm the diagnosis of MPGN.
The treatment depends on the symptoms. The goals of treatment are to reduce symptoms, prevent complications, and slow the progression of the disorder. A change in diet may be needed. This may include limiting salt, fluids, or protein to help control high blood pressure, swelling, and the build up of waste products in the blood. Medicines that may be prescribed include: 1) Blood pressure medications; 2) Immunosuppressive medications; 3) Dipyridamole with or without aspirin; 4) Diuretics; and, 5) Steroids.
Possible complications of MPGN include: 1) Acute renal failure; 2) Acute nephritic syndrome; 3) Nephrotic syndrome; and, 4) Chronic renal failure. Unfortunately, MPGN often slowly gets worse and eventually results in chronic kidney failure, with fifty percent of cases leading to chronic renal failure within 10 years. Dialysis or kidney transplant may eventually be required to manage kidney failure.
Anti-glomerular Basement Membrane Glomerulonephritis (Goodpasture's syndrome)
Goodpasture’s syndrome involves an autoantibody that specifically targets the kidneys and the lungs. Often, the first indication that patients have the autoantibody is when they cough up blood. Lung damage can range in severity, from mild to life-threatening. There is always the potential in Goodpasture’s syndrome for progressive and permanent damage to the kidneys. Goodpasture’s syndrome is a rare condition that affects mostly young men but also occurs in women, children, and older adults. Treatments include immunosuppressive drugs and a blood-cleaning therapy called plasmapheresis that removes the autoantibodies.
Minimal Change Disease
Minimal change disease (MCD) is the diagnosis given when a patient has the nephrotic syndrome and the kidney biopsy reveals little or no change to the structure of glomeruli or surrounding tissues when examined by a light microscope. Tiny drops of a fatty substance called a lipid may be present, but no scarring has taken place within the kidney. MCD may occur at any age, but it is most common in childhood. A small percentage of patients with idiopathic nephrotic syndrome do not respond to steroid therapy. For these patients, the doctor may recommend a low-sodium diet and prescribe a diuretic to control edema. The doctor may recommend the use of nonsteroidal anti-inflammatory drugs to reduce proteinuria. Angiotensin converting enzyme inhibitors (ACE inhibitors) and angiotensin receptor blockers (ARBs) have also been used to reduce proteinuria in patients with steroid-resistant MCD. These patients may respond to larger doses of steroids, more prolonged use of steroids, or steroids in combination with immunosuppressant drugs, such as chlorambucil, cyclophosphamide, or cyclosporine.
Focal Segmental Glomerulosclerosis
Focal and segmental glomerulosclerosis (FSGS) describes scarring in scattered regions of the kidney, typically limited to one part of the glomerulus and to a minority of glomeruli in the affected region. FSGS may result from a systemic disorder or it may develop as an idiopathic kidney disease, without a known cause. Proteinuria is the most common symptom of FSGS, but, since proteinuria is associated with several other kidney conditions, the doctor cannot diagnose FSGS on the basis of proteinuria alone. Biopsy may confirm the presence of glomerular scarring if the tissue is taken from the affected section of the kidney. But finding the affected section is a matter of chance, especially early in the disease process, when lesions may be scattered.
Confirming a diagnosis of FSGS may require repeat kidney biopsies. Arriving at a diagnosis of idiopathic FSGS requires the identification of focal scarring and the elimination of possible systemic causes such as diabetes or an immune response to infection. Since idiopathic FSGS is, by definition, of unknown cause, it is difficult to treat. No universal remedy has been found, and most patients with FSGS progress to total kidney failure over 5 to 20 years. Some patients with an aggressive form of FSGS reach total kidney failure in 2 to 3 years. Treatments involving steroids or other immunosuppressive drugs appear to help some patients by decreasing proteinuria and improving kidney function. But these treatments are beneficial to only a minority of those in whom they are tried, and some patients experience even poorer kidney function as a result. Blood pressure medications, most frequently, angiotensin-converting enzyme inhibitors (ACE inhibitors) or angiotensin receptor blockers (ARBs) that block a hormone called angiotensin are used in FSGS to decrease proteinuria. Treatment should focus on controlling blood pressure and blood cholesterol levels, factors that may contribute to kidney scarring.
IgA nephropathy is a form of glomerular disease that results when immunoglobulin A (IgA) forms deposits in the glomeruli, where it creates inflammation. IgA nephropathy was not recognized as a cause of glomerular disease until the late 1960s, when sophisticated biopsy techniques were developed that could identify IgA deposits in kidney tissue.
The most common symptom of IgA nephropathy is blood in the urine, but it is often a silent disease that may go undetected for many years. The silent nature of the disease makes it difficult to determine how many people are in the early stages of IgA nephropathy, when specific medical tests are the only way to detect it. This disease is estimated to be the most common cause of primary glomerulonephritis—that is, glomerular disease not caused by a systemic disease like lupus or diabetes mellitus. It appears to affect men more than women. Although IgA nephropathy is found in all age groups, young people rarely display signs of kidney failure because the disease usually takes several years to progress to the stage where it causes detectable complications.
No treatment is recommended for early or mild cases of IgA nephropathy when the patient has normal blood pressure and less than 1 gram of protein in a 24-hour urine output. When proteinuria exceeds 1 gram/day, treatment is aimed at protecting kidney function by reducing proteinuria and controlling blood pressure. Blood pressure medicines—angiotensin-converting enzyme inhibitors (ACE inhibitors) or angiotensin receptor blockers (ARBs)—that block a hormone called angiotensin are most effective at achieving those two goals simultaneously.
Thrombotic thrombocytopenic purpura (TTP) and hemolytic-uremic syndrome (HUS) are acute, fulminant disorders characterized by thrombocytopenia (low platelets) and microangiopathic hemolytic anemia (destruction of red blood cells in the circulation). Other manifestations may include alterations in level of consciousness and renal failure. Diagnosis requires demonstrating characteristic laboratory test abnormalities, including Coombs'-negative hemolytic anemia. Treatment is plasma exchange and corticosteroids in adults and supportive care (sometimes including hemodialysis) in children.
TTP and HUS differ mainly in the relative degree of renal failure. Typically, disorders in adults are described as TTP and are less likely to involve renal failure. HUS is used to describe the disorder in children, which typically involves renal failure.
In children, most cases follow acute hemorrhagic colitis resulting from Shiga toxin–producing bacteria (e.g., Escherichia coli O157:H7, some strains of Shigella dysenteriae). In adults, many cases are idiopathic appear suddenly and spontaneously without apparent cause. There are known causes and associations that should be explored, including with immunosuppressant and cancer chemotherapy drugs such as cyclosporine and mitomycin. TTP and HUS are often indistinguishable, even with renal biopsy, from syndromes that cause identical thrombotic microangiopathies (e.g., preeclampsia, systemic sclerosis, accelerated hypertension, acute renal allograft rejection). A predisposing factor in many patients is congenital or acquired deficiency of the plasma enzyme ADAMTS13, which cleaves the protein known as von Willebrand Factor (VWF) and thus eliminates abnormally large VWF multimers that can cause platelets to aggregate.
Manifestations of ischemia (lack of blood supply) develop with varying severity in multiple organs. These manifestations include weakness, confusion and coma, abdominal pain, nausea, vomiting, diarrhea, and abnormal heart rhythms (arrhythmias) caused by damage to heart tissue. Children usually will have had an initial set of symptoms including vomiting, abdominal pain, and diarrhea (frequently bloody). Fever may occur, but high fever with chills does not occur in TTP or HUS. The clinical syndromes of TTP and HUS are indistinguishable, except that neurological symptoms are less common with HUS.
TTP or HUS are suspected in patients with suggestive symptoms, thrombocytopenia, and anemia. If the disorder is suspected, urinalysis, peripheral blood smear, reticulocyte count, serum LDH, renal function tests, serum bilirubin (direct and indirect), and Coombs' test are done. The diagnosis is suggested by: 1) Thrombocytopenia and anemia; 2) Fragmented RBCs on the blood smear (helmet cells, triangular-shaped RBCs, distorted-appearing RBCs—these changes describe microangiopathic hemolysis); 3) Evidence of hemolysis (falling hemoglobin levels, polychromasia, elevated reticulocyte count, elevated serum LDH); and, 4) Negative direct antiglobulin (Coombs') test. Otherwise unexplained thrombocytopenia and microangiopathic hemolytic anemia are sufficient evidence for a presumptive diagnosis.
Testing for ADAMTS13 activity is appropriate in patients with suspected TTP or HUS, except in children who have typical diarrhea-associated HUS. Although the results of ADAMTS13 testing do not affect initial treatment, results are important prognostically. Stool testing (specific culture for E. coli O157:H7 or Shiga toxin assay) is done in children with diarrhea and also adults who had a prodrome of bloody diarrhea; however, the organism and toxin may have cleared by the time of presentation.
Treatment includes plasma exchange and corticosteroids in adults. Typical diarrhea-associated HUS in children caused by enterohemorrhagic infection usually spontaneously remits and is treated with supportive care and not plasma exchange; over half require renal dialysis. In other cases, untreated TTP-HUS is almost always fatal. With plasma exchange, however, over 85% of patients recover completely.
Plasma exchange is continued daily until evidence of disease activity has subsided, as indicated by a normal platelet count, which may be several days to many weeks. Adults with TTP are also given corticosteroids. In patients with recurrence when plasma exchange is stopped or in patients with relapses, more intensive immunosuppression with rituximab may be effective. Most patients experience only a single episode of TTP-HUS. However, relapses occur in about 40% of patients who have a severe deficiency of ADAMTS13 activity caused by an autoantibody inhibitor. Patients must be evaluated quickly if symptoms suggestive of a relapse develop.
Hereditary Nephritis—Alport Syndrome
The primary indicator of Alport syndrome is a family history of chronic glomerular disease, although it may also involve hearing or vision impairment. This syndrome affects both men and women, but men are more likely to experience chronic kidney disease and sensory loss. Men with Alport syndrome usually first show evidence of renal insufficiency while in their twenties and reach total kidney failure by age 40. Women rarely have significant renal impairment, and hearing loss may be so slight that it can be detected only through testing with special equipment. Usually men can pass the disease only to their daughters. Women can transmit the disease to either their sons or their daughters. Treatment focuses on controlling blood pressure to maintain kidney function.
Renal Amyloidosis and Non-amyloid Immunoglobulin Deposition Diseases
Amyloidosis is a progressive, metabolic disease characterized by abnormal deposits of protein in one or more organs or body systems. The characteristic feature is identified by biopsy of an involved site, and the particular pattern of staining with Congo Red dye. Related disorders not called amyloidosis are light- and heavy-chain deposition diseases, immunotactoid glomerulopathy, and fibrillary glomerulonephritis.
Proteins that cause amyloidosis and immunoglobulin deposition diseases are manufactured by malfunctioning bone marrow. Disease occurs when accumulated amyloid or non-amyloid deposits impair normal body function, which can cause organ failure or death. These are relatively rare diseases, which can affect males and females equally and usually develop after the age of 40.
The major forms of this disease are primary systemic, secondary, and familial or hereditary amyloidosis. Primary systemic amyloidosis usually develops between the ages of 50 and 60. With about 2,000 new cases diagnosed annually, primary systemic amyloidosis is the most common form of this disease in the United States. Also known as light-chain-related amyloidosis, it may also occur in association with multiple myeloma (bone marrow cancer).
The cause of amyloidosis is unknown. Most patients have gastrointestinal abnormalities, but other symptoms vary according to the organ(s) or system(s) affected by the disease. Amyloidosis can involve any organ or system in the body. The heart, kidneys, gastrointestinal system, and nervous system are affected most often. Other common sites of amyloid accumulation include the brain, joints, liver, spleen, pancreas, respiratory system, and skin.
The feet, ankles, and calves swell when amyloidosis damages the kidneys. The kidneys become small and hard, and kidney failure may result. It is not unusual for a patient to lose 20-25 pounds and develop distaste for meat, eggs, and other protein-rich foods. Cholesterol elevations that don't respond to medication and protein in the urine (proteinuria) are common.
Blood and urine tests can reveal the presence of amyloid or non-amyloid immunoglobulin proteins, but kidney, bone-marrow, or other tissue biopsy is necessary to positively diagnose these disorders. Once the diagnosis has been confirmed, additional laboratory tests and imaging procedures are performed to determine which type of protein is involved, which organ(s) or system(s) have been affected, and how far the disease has progressed.
The goal of treatment is to slow down or stop production of disease-producing protein, eliminate existing deposits, and relieve symptoms caused by heart or kidney damage. When the kidney is involved, nephrologists are important components of the treatment team. Other specialists, such as cardiologists, hematologists (who study blood and the tissues that form it), neurologists (who study the nervous system), and rheumatologists (who study disorders characterized by inflammation or degeneration of connective tissue) work together to assess a patient's medical status and evaluate the effects of amyloidosis on every part of the body.
Colchicine, prednisone, and other anti-inflammatory drugs may be used to slow or stop disease progression. Bone-marrow and stem-cell transplants can enable patients to tolerate higher and more effective doses of melphalan and other chemotherapy drugs prescribed to combat this non-malignant disease. Dialysis or kidney transplantation can lengthen and improve the quality of life for patients whose amyloidosis results in kidney failure.