What is IgA?

Immune complexes form when the body is exposed to an antigen, such as a virus, bacteria, toxin, or even allergen. In response, your body sends out antibodies, which are immunoglobulins produced by a certain class of white blood cells known as B-cells. There are five main classes of these immunoglobulins, with IgA [immunoglobulin A] being the main one directed against bacterial and viral antigens.

Antibodies lock onto the surfaces of viruses and other foreign cells, producing antigen-antibody aggregates known as immune complexes that your body targets and attacks. Normally, these immune complexes circulate through the bloodstream until being removed by the liver and other organs. In IgAN, however, they become trapped in the glomeruli.

Once trapped, immune complexes become like magnets for the rest of the body’s immune response. Macrophages and other cells race to the area to release enzymes and generate toxic oxygen radicals that kill bacteria and viruses but also injure local tissues. Trapped immune complexes can also stimulate the overproduction of extracellular matrix, a substance which surrounds and supports tissue cells. Inflammatory chemicals released during the immune response increase the permeability of the glomerular capillary walls, causing blood being filtered in the kidneys to leak protein and fibrinogen. Fibrinogen, crucial to the process by which blood clots, develops into “crescents,” which form scar tissue that obstructs circulation through the glomerulus. Eventually, deprived of blood, the tubules and glomerulus die, thus destroying the nephron and forcing other nephrons to take up its work.

What happens in IgAN is essentially a vicious cycle: inflammatory chemicals increase the permeability of the glomerular capillary wall, and that increased porosity enhances the absorption of other chemicals that stimulate cellular growth and, ultimately, structural damage. These changes take time because our kidneys have a lot of excess capacity built into them. The damage is, however, slowly progressive and, in the case of sclerosis [scarring], irreversible.

We do not know what antigen is responsible for triggering IgAN, nor do we know whether IgAN results from defects in the body’s creation or elimination of immune complexes. There is evidence that immunoglobulin A is overproduced in the bone marrow of IgAN patients; some patients also show decreased capacity to remove immune complexes from their systems.

Because so many IgAN patients have a cold or gastrointestinal illness shortly before the onset of symptoms in the kidneys, it is likely that IgAN starts with an immune response to infectious agents. Perhaps protracted exposure to antigens — as in a recurrent viral illness, or the multiple illnesses experienced by some IgAN patients — sends the immune system into overdrive. The blood of IgAN patients often shows high concentrations of IgA antibodies to a type of protein found in many bacteria, as well as antibodies to many viruses. Certain viruses, once established in the body as a low-level chronic infection, could serve as a continuing source of antigen for the formation of additional IgA immune complexes — and for the perpetuation of injury to the kidneys. It is quite common for IgAN to present after an individual has had an illness such as strep throat, ear infection, etc., that was treated with antibiotics. Antibiotics are effective against bacteria but not against viruses and can even suppress the immune system as far as viral infections are concerned, perhaps allowing a viral infection to become chronic.

Viruses can also over-sensitize the immune system, inducing autoimmune reactions in which the body becomes allergic to itself. Few IgAN patients, however, show a positive anti-nuclear antibody test [ANA], which is an important tool in diagnosing such autoimmune diseases as systemic lupus erythematosus.

It’s clear that IgAN is not simply a kidney disease but rather an immunological disorder that affects the kidneys, as diabetes is an immunological disorder that affects the pancreas. It may also be a disease, like diabetes, that affects the micro blood vessels. If true, this would explain some common extra-renal symptoms, such as headaches, temporary vision problems, and difficulties concentrating.

People who have IgAN rarely have a history of kidney disease in their family. Often, however, there is a personal or family history of other immunologically-mediated disorders, such as psoriasis, asthma, or celiac-sprue, especially if these have been treated with such immunosuppressive medications as corticosteroids. If the family’s medical history includes such disorders, or if other family members have experienced “brown urine” or excessive fatigue, the Network recommends screening the blood pressure and urine of all family members.

There is no proven treatment for IgAN. Your doctor’s recommendation as to whether to treat or not probably will be based on three factors:

The severity of the lesions, as revealed by the biopsy;
The degree of proteinuria (usually proteinuria greater than 2,000 mg/day warrants treatment);
The creatinine clearance (if less than 70 ml/min [milliliters per minute], treatment is generally recommended).

Doctors usually try to curb the acute inflammation signaled by heavy proteinuria. In severe cases, some employ high intravenous doses of methylprednisolone, a glucocorticoid that is anti-inflammatory and immunosuppressive. This is called “pulse therapy,” and it is usually employed for only short periods. In less acute cases, most physicians use oral corticosteroids, like prednisone, which are also anti-inflammatory and which help to stabilize the glomerular basement membrane, making it less permeable to large protein molecules. Prednisone is given either daily or every other day to minimize its toxic side effects.

Unfortunately, prednisone does not work in all cases, not is there any proof that it does much more than temporarily slow the disease process. Prednisone (or any corticosteroids) has potentially serious side effects when used long-term (e.g., bone damage and necrosis [tissue death], weakening of arm and leg muscles, peptic ulcers, diabetes or hyperglycemia, increased susceptibility to infection, cataracts, acne, weight gain, manic or even psychotic behavior, and lesser “cosmetic changes” such as a moon face). Its use needs to be thoroughly discussed with your nephrologist. Some doctors report that patients on prednisone seem to feel better than untreated patients, perhaps because prednisone makes them feel “up” and energized. On the other hand, some believe that using prednisone reduces chances of having a natural remission.

Because immunosuppressants can reactivate even dormant viruses, transplant candidates are routinely tested for viruses. But IgAN patients in the early stages of the disease are not. Before going on prednisone or any other drug that suppresses the immune system, it is vital that you be tested for tuberculosis and for the possibility of a viral infection. Rather than testing for individual viruses such as Epstein-Barr (EBV), cytomegalovirus (CMV), or various herpes viruses, your doctor may want to order an immunoradiometric assay of alpha-interferon levels in your. An antiviral glycoprotein, alpha-interferon is usually undetectable in the blood of normal individuals; its presence, usually in high concentrations, is a fairly reliable indicator of a viral infection. Also inform your doctor if you’ve never had such diseases as measles or chickenpox or mumps. Immunosuppressive drugs can turn a mild childhood disease into a major threat.

Other treatments than prednisone, based on other rationales, have been tried with little or no success. The anti-convulsive drug phenytoin (Dilantin) was found to lower levels of circulating IgA in the blood, but did nothing to alter the course of the disease. Anti-coagulants like warfarin and platelet inhibitors like dipyridamole have been employed, usually in combination with other drugs, because excessive clumping of blood platelets in the glomerular capillaries is suspected of being an accessory in damaging the kidneys. A gluten-free diet, adopted to remove food allergens that might be triggering the body’s immune response, had some success but was difficult for many to follow. More recently, a low-antigen diet has shown promise. [See Should I follow a special diet?]

Cytoxic drugs used in chemotherapy, like cyclophosphamide (Cytoxan), and drugs used to prevent organ rejection in transplants, such as azathioprine (Imuran) and cyclosporine (Sandimmune), are powerful immune suppressants that carry unacceptable risks for all but the most relentless cases. Unfortunately, the Network has received a number of reports over the years of such drugs being used on children without their parents being fully informed of the potential consequences, such as sterility. If you are not informed of ALL potential side effects of a treatment, there is no such thing as “informed consent.”

Plasmapheresis [a process in which such blood constituents as red blood cells are separated from the plasma and returned to a patient’s system] is widely used in Japan to treat immune-complex mediated diseases like IgAN, but doctors here question its usefulness. Removing immunoglobulins from the blood makes a patient more vulnerable to serious illness. It also removes clotting factor, raising the risk if hemorrhage in the event of injury. On the other hand, in cases of rapidly progressive IgAN, combinations of steroids, cytoxic drugs, and plasmapheresis may be helpful, at least temporarily.

Another treatment that has enjoyed a certain vogue is the tonsillectomy. This may help those who are prone to sore throats and infected tonsils, but there is no proof it affects the course of IgAN. Chronically infected tonsils can also be treated by non-surgical means, such as homeopathy.

You should discuss with your doctor ALL the potential side effects of any therapy proposed and carefully weight possible risks against possible benefits. There is no real proof that any currently used medical therapy is of any value in treating IgAN, at least among those who do not have the rapidly progressive form. Some have shown promise in ameliorating symptoms. None is curative.

In relatively mild cases of IgAN, your doctor may recommend treatment with fish oil high in eicosapentanoic acid [EPA], which has anti-inflammatory properties and which may also lower plasma triglycerides and cholesterol. Results have been mixed, but many doctors believe this can be an effective anti-inflammatory if started early. [See Fish Oil] Fish oil is unlikely to have harmful side effects, but it does have anti-coagulant properties that can exacerbate heavy cases of gross hematuria. Of greater concern is the possibility of heavy metal or dioxin contamination, especially at the “standard” adult dosage of a whopping 12 g/day. You might wish to consider starting with a substantially smaller dose, such as 3 g/day, to see if produces the desired effects of reducing inflammation and proteinuria. Another possibility is to use flaxseed oil or perilla oil as alternatives. From vegetable sources, these oils are free of heavy metal or dioxin contamination, are high in EPA, and are more easily tolerated than fish oil, although you may need to take more of them to acquire the same concentrations of EPA. (A recent Consumer Reports survey of fish oil capsules found none that contained “significant” amounts of mercury, PCBs, or dioxin.)

Because it is vital to treat hypertension if that is present initially or develops, your doctor may prescribe anti-hypertensive medication. Uncontrolled hypertension is strongly linked to more rapid progression of IgAN, perhaps because excessive pressures within the kidney strain already damaged glomerular capillaries. Hypertension can often be managed successfully through weight loss, low-fat diet, and regular aerobic exercise; in kidney disease, however, your doctor may have to try several medications before finding the right one.

Diuretics are perhaps the least effective in controlling hypertension associated with renal disease. ACE inhibitors like enalapril (Vasotec) or ramipril (Altace) or beta-blockers are usually a better choice. They have been found to reduce the risk of kidney failure when compared to calcium channel blockers also used to control hypertension.

Studies suggest that ACE inhibitors, by inhibiting the formation of the hormone angiotensin, help preserve the integrity of the glomerular membranes, making them less permeable and thereby decreasing proteinuria. They may also lessen the scarring of kidney tissue by interfering with the process that stimulates mesangial proliferation [excessive growth of mesangial cells]. Many doctors use ACE. inhibitors prophylactically, administering small doses even before hypertension appears. Dosage must be carefully monitored to avoid hypotension [extremely low blood pressure] and dizziness. The long-term effects of using ACE inhibitors in children are not clear. Patients may develop a chronic cough on the medication and have to switch to another anti-hypertensive drug.

Hyperlipidemia is also associated with renal disease, and your doctor may wish to treat that with dietary changes or cholesterol-lowering drugs. It is important to reduce cholesterol levels to prevent heart disease; moreover, high cholesterol levels may aid the progression of IgAN. When lipids accumulate in the kidneys, possibly following injury to the mesangium, they are believed to contribute to scarring of the glomeruli. Again, treatment is a topic to be thoroughly discussed with your doctor. Cholesterol-lowering drugs, such as statins, can have dangerous side effects, including liver damage, memory loss, and rhabdomyolysis [a potentially fatal disease marked by destruction of skeletal muscle].

For a detailed discussion of statin drugs and other traditional means of lowering cholesterol, as well as alternatives to these, see the Life Extension Foundation, “Cholesterol Reduction” ( http://www.lef.org/protocols/prtcl-032.shtml ). The Life Extension Foundation sells nutritional supplements, but their research is thorough and reputable. Redflagsdaily.com, a health-oriented website started by Nicholas Regush, a Canadian journalist specializing in medical and scientific issues, has also explored problems with statins and other drugs; but to access this material requires subscribing the site.

Kidney diseases of all types affect over 13 million Americans, killing about 78,000 each year. In 1989, Medicare’s End-Stage Renal Diseases Program accepted nearly 42,000 new patients, primarily for dialysis. Of these, 13.1% had glomerulonephritis, which ranks behind only diabetes and hypertension as a contributor to renal failure.

Although glomerulonephritis is a major cause of kidney failure — and IgAN is by far the most common glomerulonephritis — we have no firm idea how many people are affected by IgAN. One reason for this is that definitive diagnosis of IgAN is possible only by biopsy, but biopsies are not conducted routinely for mild urinary abnormalities. Another reason is that there is no separate ICD (International Classification for Diseases) code for IgAN. Hospitals use these codes to classify their diagnoses, and government agencies use such data to track the incidence [number of new cases each year] of various diseases.

In 1991, the Centers for Disease Control (CDC) estimated that the prevalence [total number of cases] of IgAN was small in the United States, perhaps on the order of 5,000 people. The next year the CDC raised that estimate to 150,000. This does not mean that we have a sudden epidemic of IgAN in America; it does mean that public health officials are becoming more aware of this disease and concerned about its potential impact.

According to Medicare data for 1986-1989, glomerulonephritis causes approximately 5,500 cases of kidney failure each year. The National Institutes of Health’s Division of Kidney, Urologic & Hematologic Diseases believes that the “overwhelming majority” of those diagnosed with glomerulonephritis have IgA Nephropathy. Others estimate that IgAN is responsible for 10-20% of all end-stage renal disease. These estimates suggest that IgAN may be sending 2,800 to 4,200 Americans into renal failure each year.

The prevalence of IgAN is thought to be lower in North America than in Asia, Australia, and parts of Europe, but it is not clear whether this difference is real or merely reflects an understandable reluctance by doctors in the U.S. to submit patients to biopsy for signs such as asymptomatic microhematuria [traces of blood in the urine with no other symptoms].

In the United States, up to 5% of renal biopsies examined by immunofluorescence are diagnosed as IgAN. Yet in Japan, where schoolchildren have a mandatory urinalysis each year, and in Singapore, where all young men are screened for military service, IgAN accounts for up to 50% of glomerulonephritis cases. These are among the highest rates in the world, but whether they reflect a genetic predisposition to the disease, or environmental factors, or simply better screening and earlier diagnosis, no one knows.

Similarly, Finland, which also screens its young men for compulsory military service, detects an average of 22 cases of IgAN per 100,000 young male population per year. Presumably, this does not include cases found among females or older men, although IgAN typically strikes more men than women (the ratios vary by country) and strikes most often in the very early teens or twenties. Other European nations, like Scotland, are finding they have more IgAN than previously supposed, and this is probably happening in the United States as well.

IgAN is seldom seen in blacks, although its presumed rarity in Africa may be owing to underdiagnosis. In areas like Singapore, there is no significant difference in incidence among the Malay, Chinese, and Indian populations. American Indians, especially the Zuni, have an unexpectedly high incidence of IgAN, but, again, whether due to genetic or environmental factors, no one knows. Even among Native Americans, some doctors believe the incidence is grossly underestimated because so many Indians do not receive proper medical care or are never biopsied.

In the U.S., IgAN is considered an “orphan disease,” one affecting fewer than 200,000 people. Underestimated though its prevalence may be, IgAN will no doubt always be viewed as a rare disease. That makes it more difficult to attract governmental and private funding for research, to conduct trials of various treatments, and to link patients for mutual support.

Seen in a toilet bowl, diluted by water, this dark urine may give the impression that you’re dehydrated. But urine from dehydration is dark yellow or orange in color, whereas urine from macrohematuria has a dark green or black tinge. If there is any doubt, void into a clear plastic cup: the differences in appearance between macrohematuria and dehydrated urine are more striking there than in the toilet bowl.

We do not know what causes hematuria or what its presence in the urine means. Although gross hematuria may look scary, patients who have it generally are considered to have a better prognosis than those with persistent microhematuria. Those presenting with gross hematuria will probably have recurrences at intervals ranging from months or years, with the intervals growing longer over time. Even those who did not initially experience gross hematuria are likely to have an episode at least once. Episodes are often closely associated with a respiratory infection, less frequently with a gastrointestinal infection, strenuous exercise, or vaccination.

During episodes of gross hematuria, it is important to drink lots of pure water to prevent the formation of tiny blood clots that can behave much like kidney stones and potentially cause pain. Expect to feel generally rotten during the course of an episode. An episode’s length varies from patient to patient, but most last a few days.

A very, very few patients experience constant gross hematuria of pure blood. Their urine looks red rather than smoky. Such patients should NOT use fish oil or any medication that acts as an anticoagulant (including aspirin), as it can worsen their bleeding.

Proteinuria is the leakage of protein into the urine. Ordinarily, the glomerular capillary walls behave like a fine sieve, but inflammation in effect loosens the sieve’s mesh, allowing larger molecules to escape. The normal glomerular capillary wall is charge-selective as well, for portions of its basement membrane carry a negative electrical charge. This becomes neutralized in IgAN, possibly by positively-charged enzymes released by inflammatory cells. When this occurs, the capillary walls no longer repel negatively-charged protein molecules, allowing some to escape into the urine.

A person can be considered healthy and still excrete a small amount of protein in the urine (up to 150 mg/day [milligrams per day], or 0.15 g/day [grams per day]). Losing more than that is abnormal. Proteinuria is usually defined as heavy (over 3,000 mg/day), moderate (1,000-2,900 mg/day), and mild (under 1,000 mg/day). Many patients with IgAN, especially children, have only mild to moderate proteinuria.

Proteinuria can also be “selective” (containing only proteins of certain molecular weights) or “nonselective” (containing mixed-weight proteins). Generally speaking, those patients with selective proteinuria, especially if almost exclusively albumin, have a better prognosis than those whose urinary protein contains mixtures of high and low molecular weights.

Proteinuria will often start out heavy when the disease first appears. Like hematuria, it can be exacerbated by respiratory or other illnesses, or even by emotional stress.

If protein loss rises to heavy levels during the course of IgAN and remains high, this is usually as sign of a poor prognosis. Heavy proteinuria often precedes the development of hypertension (see below). When protein loss is massive (usually over 3 g/day), it can provoke nephrotic syndrome, symptoms of which include edema, fatigue, anorexia [unwillingness to eat], abdominal pain, and wasting of muscles. If left untreated, heavy urinary loss of certain proteins, as well as of immunoglobulins and hormones, can lead to nutritional deficiencies, bone demineralization, and a high incidence of infections.

IgAN was thought relatively benign when it was first identified in 1968 by the French doctor, Jean Berger, but gradually researchers realized that in up to 50% of the cases, the disease very slowly progresses to end-stage renal failure, requiring major lifestyle changes, dialysis, and possibly transplantation.

IgAN does not immediately interfere with the kidneys’ filtration work — except in acute cases — but it may threaten it ultimately. Damage results as kidney tissue gradually develops irreversible scarring, which ultimately blocks renal capillaries, causing the death of surrounding tissues as these are deprived of blood and nutrients. The slow accumulation of these tiny affected areas can take ten or twenty — or more — years to produce kidney failure, although a small minority of patients, mainly adults, have a rapidly progressive form that results in renal failure within a few years or even months.

As individual capillaries become clogged by coagulation excessive cell growth, or infiltration by inflammatory cells, the nephron loses filtering surface. The kidneys’ glomerular filtration rate [GFR], a measure of how efficiently the kidneys filter blood, declines when that loss is enough to overcome the body’s efforts to adapt by increasing pressure throughout the remaining nephrons. As GFR decreases, the kidneys nose their ability to cleanse the blood of toxins and metabolic byproducts. Kidney failure and uremic poisoning result.

It is difficult to predict from initial clinical signs and biopsy results just which patients will have which course. Statistical analyses have yielding conflicting results, but some factors do seem linked to a poor prognosis. Unremittingly heavy proteinuria, uncontrolled hypertension, declining glomerular filtration rate, high serum creatinine, and being age 30 or older at the time of apparent onset of the disease are some of the factors tied to a poor prognosis. Severe lesions in the initial biopsy, especially evidence of sclerosis [scarring] or crescent formation are also ominous signs.

Except for the very few who have rapidly progressive IgAN, most patients will take years, even decades, to develop kidney failure. Those who have end-stage renal disease [ESRD] are treated with dialysis and may be candidates for transplantation. Deposits of IgA, the hallmark of the disease, frequently appear in transplanted kidneys, but the clinical symptoms do not usually come back. An early survey of transplants due to IgAN showed that although IgAN-type lesions recurred in over 50% of the respondents, only 3% lost their new kidneys to a resurgence of the disease.

More recently, doctors have observed deposits of immunoglobulin A in up to 80% of patients who have received transplants after their own kidneys were destroyed by IgAN; yet only one quarter of these showed any clinical symptoms. About 20% of those transplanted lose their grafts to recurrent IgAN. According to one nephrologist who has followed this subject, graft failure came generally after 8-10 years, which would be the expected lifespan for a cadaver kidney anyway. In other words, recurrent IgAN did not contribute to early, unexpected loss of a transplant.

The possibility of recurrent IgAN should not discourage patients from having a transplant, but they should be aware that a transplant is not a cure for the disease, merely a replacement organ.

Occasionally the Network has encountered families with two or more cases of IgAN, but in our experience this has generally been sex-linked (e.g., mother-daughter, uncle-nephew).

Whether your low-salt diet is very strict (no more than 1,000 mg of sodium per day), or more lenient (2,000 mg per day), you will probably have to eliminate certain favorites, namely, all fast foods, pizza, cheesesteaks, hoagies, prepared snacks, etc. Plan on becoming an avid label-reader. Health food stores and most supermarkets offer low-salt or no-salt substitutes for some items (catsup, mayonnaise, deli meats and cheeses, salad dressings, crackers, cookies, potato and taco chips, soups, candies, etc.). They also offer assortments of herbs that can be used in lieu of salt (not to be confused with commercial salt substitutes that rely on potassium in place of sodium; these are not recommended).

You may find it easier to put the entire family on a low-salt regime, so the patient doesn’t feel “left out.” It’s healthier for everyone, but it does take cooperation on the family’s part and flexibility on the cook’s. Paradoxically, the new diet may be more easily accepted if you radically revamp your cooking style rather than trying to remake old favorites or introduce low-sodium analogs to familiar foods. Ethnic cuisines that rely heavily on herbs or citrus juices — for example, Italian, Mexican, and Thai — are more easily adapted to low-salt cooking.

Another possibility is to adopt a basically vegetarian diet. Those with moderate to heavy proteinuria should strongly consider eliminating meat and milk products, basing their diet upon fresh fruits and vegetables, whole grains, and such vegetable sources of protein as nuts, beans, legumes, soy, and fish, while avoiding processed or fast foods. This type of diet saves the kidneys a lot of hard work in clearing the body of the byproducts of metabolizing animal proteins. There are also chemicals in milk and meat that exacerbate the inflammatory process taking place in the kidneys.

There are no cookbooks specifically for IgAN patients, but there are many fine vegetarian as well as low-salt cookbooks available. [For a list of recommended ones, see Vegetarian Cookbooks] When evaluating cookbooks, it is important to use ones that do NOT rely on dairy products as a substitute for meat.

In the later stages of kidney failure, patients are put on very restricted diets. There are various types, depending upon how much renal function has been lost, but most limit protein and potassium intake. Some doctors believe a low-protein diet should be adopted much earlier to spare the kidneys and slow down the disease process, while others advocate eliminating dairy products because milk proteins irritate the immune system.

It used to be thought that a low-protein diet worked to preserve kidney function by reducing pressures within the glomeruli, but recent animal experiments suggest that it helps suppress the expansion of extracellular matrix that occurs in glomerulonephritis — and that is implicated in the scarring of the glomeruli. A diet based on vegetable proteins from beans, lentils, grains, and nuts is rich in “good” fatty acids, which can help dampen the inflammatory response that damages the kidneys in IgAN. [For more information, see Not What We Expected.

Often patients with IgAN have multiple allergies or a family history of other immunologically-mediated problems, such as asthma. An Italian study reported a marked reduction in proteinuria in IgAN patients put on a strict low-antigen diet [a diet free of foods likely to cause an allergic reaction]. Such diets, which have also proved effective in treating Attention-Deficit Disorder, may exclude such commonly allergenic foods as wheat, corn, soy, food preservatives, and food coloring agents. Excluding allergenic foods has become more difficult in recent years because of the rise of genetically-modified foods that may contain foreign proteins capable of triggering an allergic reaction. For highly sensitive people, eating certified organic foods may be the only way to avoid genetically-modified foodstuffs.

Food allergies can be difficult to detect by observation, because people may have a delayed reaction to — or even a craving for — foods to which they are allergic. The least expensive way to approach this problem is to go on an elimination diet in which allergenic foods are removed, then slowly rotated back into the diet, one at a time. A more expensive, but also more thorough approach, is to be tested for delayed hypersensivity reaction through an ELISA/ACT test. [For more information, see Dampening the Inflammatory Response. ]