| What is IgA Nephropathy? Think of your kidneys as small but powerful filtration plants whose job is to keep your blood clean and the body’s chemical balance maintained. Each day the kidneys process about 200 quarts of fluid through their two million tiny treatment plans, the nephrons. Within the nephron is the glomerulus, a tangle of fine capillaries that filter the blood before passing it on to the tubules, where the kidneys continually adjust the filtrate to your body’s needs, adding back chemicals removed during filtration or drawing off more water. What’s needed by the body is returned to the bloodstream; what’s not needed is excreted as urine. In IgA Nephropathy [IgAN], unknown agents cause the glomeruli to become — and to stay — inflamed. IgAN is the world’s most common glomerulonephritis [inflammation of the glomeruli], but its pathogenesis [how the disease develops] is not known. IgAN is considered to be an immune-complex mediated disorder (or immunologically mediated disorder), which means that immune complexes may not be the direct cause of the disease but they help bring about the end result, which is widespread inflammation of the kidneys. 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. ^^^top^^^ How is IgA Nephropathy diagnosed? In countries like Japan, where routine urinary screening of school children is required by law, the disease is often picked up at a very early stage by the presence in the urine of protein [proteinuria] or of microscopic amounts of blood [microhematuria]. In the United States, it is most commonly discovered after a child or adult passes a strange urine discolored by blood [gross or macrohematuria] so it looks like murky Coca-Cola or tea. In the West, IgAN tends to be discovered more readily among girls, perhaps because they are at greater risk for urinary tract infections and more likely to undergo urinalysis than boys. Blood in the urine can be caused by many things. Because so few doctors are familiar with IgAN, a patient may be put through extensive urological tests to determine if there is a urinary tract infection or congenital abnormality. But if the red blood cells in the urine are examined under a microscope, they appear dysmorphic [strangely shaped]: instead of being full and round, they look as if they’d been nibbled around the edges. This is a tip-off that glomerulonephritis is involved, but it does not tell the doctor which glomerulonephritis it might be. A physician may first believe that this is post-streptococcal glomerulonephritis [PSGN], a disease that resembles IgAN in some ways (but which, unlike IgAN, tends to resolve itself spontaneously). To assist the diagnosis, the doctor performs a variety of tests, including a complete blood count, blood-urea-nitrogen [BUN], serum creatinine, and ASO titers to rule out the possibility of post-streptococcal glomerulonephritis. Your doctor may also order a creatinine clearance test. Based on a 24-hour urinalysis, this test ascertains how well they kidneys are performing their vital task of clearing creatinine, the end product of muscle metabolism, from the blood. The results show the kidneys’ glomerular filtration rate. This test is not diagnostic of a particular disease but, rather, of the severity of the inflammation and, possibly, the extend of damage to the kidneys. Your kidneys ordinarily filter about five ounces of blood each minute, but in IgAN, the filtration rate may decline because infiltration of the glomerular capillaries by inflammatory cells reduces the amount of surface area available for filtering work. Blood and urine testing and the absence of certain hallmarks of other kidney diseases, such as azotemia [excessive nitrogen in the blood] and pronounced edema [swelling of tissues from retained fluid], may suggest IgAN, but only a biopsy can confirm it. ^^^top^^^ Is a biopsy really necessary? Probably not. If a case seems mild, a doctor may recommend following it through periodic office visits. If the clinical symptoms are severe, however, a doctor is more likely to recommend a biopsy. Only by examining tissue samples under light and electron microscopy and immunofluorescence can doctors confirm a presumptive diagnosis of IgAN. If a patient has IgAN, deposits of IgA [immunoglobulin A] show up in a definite pattern within sections of the glomeruli, usually the mesangium. Perhaps more important, only by examining samples of kidney tissue can doctors tell how much damage has occurred. The nature and extent of damage are important in determining the likely prognosis [outcome of the disease]. In theory this should influence the doctor’s choice of treatment, but in practice it rarely does. Ask your doctor whether having a definitive diagnosis from a biopsy is likely to make any difference in his approach to treating IgAN before agreeing to a biopsy. Biopsy specimens of IgAN patients show a wide variety of lesions [changes to the structure of tissues], the most common being mesangial proliferation, in which the mesangium supporting the glomerular capillaries becomes widened by excessive growth of matrix. The pattern can be focal [affecting all of a few glomeruli in an area], or segmental [affecting only certain parts of the glomeruli], or diffuse [affecting all of every glomerulus]. Damage can affect other parts of the nephron, such as the tubules or Bowman’s capsule, which houses the glomerulus. Under immunofluorescence, technicians see IgA deposited in granular patterns. Other immunoglobulins, complement, and fibrin may also be present, as well as evidence of sclerosing [scarring]. The more severe the clinical findings — especially if proteinuria is very high — the more severe the biopsy results are likely to be. Because there is no uniform system for grading biopsy specimens (and because the terms used are confusing even to researchers), it’s a good idea to discuss the biopsy results thoroughly with your doctor and get an explanation of the grading system used by the laboratory in evaluating the lesions. Needless to say, you should also obtain a copy of the biopsy report for your medical records. The renal biopsy almost always used in the U.S. is the percutaneous, in which a tiny core of tissue is removed through a hollow biopsy needle inserted into the kidney through the back. To guide the needle into place, the doctor uses such techniques as intravenous pyelography, radionuclide scans, fluoroscopy, and especially ultrasound (which involves no radiation exposure). Done under sedation and local anesthetic, percutaneous biopsy involves an overnight stay at the hospital. Although a renal biopsy is considered a minor surgical procedure, it can create complications. Risks include developing an infection or having bleeding around or within the kidney, with subsequent development of a hematoma [a swelling filled with blood]. It is possible that pressure from a large hematoma might hasten deterioration of the kidneys. A more likely problem, however, is that the nephrologist might not obtain enough tissue from the glomeruli for adequate analysis. Because the risk of complications is higher in pediatric biopsies (about one-third of these experience complications), it is important to weigh carefully whether a biopsy is REALLY necessary in the case of a child, especially a young one. Some hospitals permit parents to attend biopsies, but this is not something to be undertaken lightly, for it can be upsetting to watch your child reacting to the needle, even though under sedation. If at all possible, parents should stay with a child after a biopsy, because there is likely to be some post-op pain and discomfort. For anyone undergoing a biopsy, it is important to drink plenty of water or juices in the hours following the procedure. ^^^top^^^ How does one get IgA Nephropathy? At present, we don’t know how the disease is contracted, or how it develops, or how to protect ourselves against it. We do know that it is not contagious. Its development may be linked to possible genetic defects in immune response or immune-complex clearance. By themselves, these do not cause disease. Some type of antigen must be present in the body, perhaps bacterial (streptococcus), or viral (influenzas of certain type), or endogenous (produced by the body itself). Genetic programming, however, may make some individuals more susceptible to developing IgAN upon exposure to certain antigens. 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. ^^^top^^^ How many people have IgA Nephropathy? 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. ^^^top^^^ What are the major symptoms of IgA Nephropathy? The most frequently seen symptoms are proteinuria and hematuria. Hematuria is the presence of blood in the urine, either as scattered cells discernible only by microscopic analysis or chemical tests (microhematuria), or visible to the eye as a darkening of the urine (macro- or gross hematuria). Rarely in episodes of macrohematuria does the urine look red or "bloody"; usually it is tea-colored or smoky. It may also have a strong smell. Red blood cells predominate; the presence of white cell casts usually indicates inflammation of the glomeruli. 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. ^^^top^^^ What other side effects or symptoms does IgA Nephropathy have? The dominant complaint of most patients is of fatigue, which can be overwhelming. They may have a sore throat (which should be tested for strep), or a headache, or some other problem, but none of the overt symptoms is sufficiently grave to explain how bad they feel or how tired they are. Exhaustion can make it difficult, even impossible, to concentrate, do schoolwork, or perform their job. Episodes of apparent illness combined with fatigue can last for several days or more. There is no way to predict when or how often they will strike or how long they will last. During these episodes, patients may have a peculiarly strong and foul breath, loss of appetite, dry skin, pallor, weakness, inability to concentrate, and shortness of breath. Unfortunately, IgAN’s side effects are not well documented in the medical literature, so many nephrologists are unfamiliar with many of the problems the disease can cause. One authority notes that there are few apparent symptoms in the disease, although among those that do occur during episodes of gross hematuria are malaise [feeling of weakness and lethargy], low-grade fever, flulike symptoms, flank pain, and myalgias [pain in the muscles]. Patients report, however, that these symptoms can occur without hematuria. Episodes of gross hematuria and rises in proteinuria often seem triggered by colds or other respiratory infections, or even by lack of sleep. At other times there is no apparent trigger. Some patients have sore throats and headaches as if coming down with a cold, yet they have no fevers and tests for bacteria are negative, suggesting that a virus — or an autoimmune reaction — may be involved. Emotional stress may also aggravate proteinuria, at least temporarily. (Even hereditary disorders like hemophilia have their symptoms exacerbated by stress.) It may look as if the patient is immune-deficient and falling prey to every bug that comes along, yet full-blown symptoms of respiratory illness (sneezing, runny nose, cough) rarely develop. IgAN seems to follow a seasonal pattern, worsening in winter and spring. Patients report an increased number of "colds" then, but it is unclear if these are actual viral/bacterial infections or hyperimmune reactions. Many also report that it takes them a month or more to get over colds that other family members shake off in days. In general, patients with IgAN seem to need much more sleep (12 hours or more a day) than most people. Most patients find that they tire more easily and have much less stamina than formerly. We have had reports of children losing sensitivity to temperature change so they do not feel the cold and tend to underdress; this has not yet been confirmed in adults. Developing allergies or contrary reactions to medications is more common among both children and adults. Some patients seem to go from wellness to illness within as little as an hour or less, as if experiencing an allergic reaction. Many patients have bouts of flank pain, which can range from a dull ache in the back (often confused with lower back problems or arthritis) to debilitating spasms that make walking and rising difficult. Hypertension [high blood pressure] is not usually found when IgAN is first diagnosed, but it often develops in the course of the disease. Because of the kidneys’ important role in controlling blood pressure (by releasing enzymes that tell blood vessels to relax or constrict and by excreting excess salt), hypertension is a frequent complication of most kidney disorders. Hyperlipidemia [excessive fat lipids in the blood] and elevated cholesterol levels are also very common in diseases that, like IgAN, involve immune reactions. Some patients, especially children, experience occasional excruciating abdominal pain that may be mistaken for appendicitis. Unlike appendicitis, however, the white blood cell count is not elevated, there is no fever, and an ultrasound scan of the abdomen, while painful, may show only swollen lymph nodes. This abdominal pain has also been mistaken for renal colic [severe pain produced by passage of a kidney stone], or, in women, a ruptured ovarian cyst. You may notice mood swings: patients with IgAN can become hyper-irritable, querulous, demanding, although within a few days, as their strength returns, so does their sense of humor and their good nature. When feeling ill, they can become very pale, with large, dark circles under the eyes. Some also have periorbital edema [swelling from retained fluid around the eyes] in the morning and swelling of the ankles in the evening. Because IgAN so often seems to appear after a series of seemingly unrelated illnesses (for example, pneumonia, mononucleosis, strep throat, middle-ear infections, etc.), an underlying viral infection may be present. Allergic reactions may also complicate IgAN and be reflected in some of its symptoms. Many IgAN patients seem prone to developing itchy, hives-like rashes [urticaria] over large areas of their bodies. The cause of this is not known, but it may be associated with deposition of immunoglobulin A in the skin. ^^^top^^^ If I experience flank pain, how should I treat it? Flank pain often starts as a little discomfort in the area above one or both kidneys. It may feel as if a nerve is pinched in that area, and the skin over the kidneys may be very sensitive to the touch. If the area over the kidneys is sore — but not the area over the spine — you should suspect flank pain. There are no good medical treatments for flank pain. Aspirin can aggravate bouts of gross hematuria, and doctors warn against using it in children and teenagers whenever there is a possibility of a viral infection because of the danger of developing Reye’s Syndrome. Acetaminophen (Tylenol) and ibuprofen (Motrin, Advil) are both nephrotoxic and should not be taken in quantity for any type of pain, including headaches. Besides, painkillers appear to have little effect on flank pain. Similarly, sedatives and muscle-relaxants like Valium do little once an attack is underway, nor is there evidence that such heavy-duty painkillers as Demerol or nerve blocks are effective. Hypnotherapy, biofeedback, and acupuncture are useful in managing certain types of pain, but there is no information yet on whether any of these works with flank pain. Homeopathy is most likely to offer symptomatic relief that is also safe and non-toxic. The simplest approach to handling flank pain is to catch it at the start and apply heat to the area with a hot water bottle, heating pad, or soaks in a warm bath or shower. Hot castor oil packs over the affected area may be helpful, if messy. Try to increase fluid intake during attacks. If you have frequent attacks, especially of severe spasms of pain, watch your morning urine specimen carefully. If it is turbid [very cloudy] with a fine, white sediment, consider taking yourself off ALL dairy, ALL meat products, and ALL sodas until the urine clears and the pain ends. Stay away from refined sugar; use lots of fresh fruit and vegetables and only WHOLE grains. We have no proof that this regimen works for all, but it is worth a try if you are in severe pain. It’s also a good idea to stay away from caffeine, alcohol, and tobacco during any exacerbations of the disease. The Network has also received reports that repeated bending and overuse of the back may aggravate flank pain. If this is a feature of yours work, you may need to speak to your employer about possible modifications to your job. As with so much of IgAN, we do not know what causes flank pain, and not knowing the cause makes treatment largely a matter of experimentation. If you’ve found something that works for you, we welcome your suggestions. ^^^top^^^ What happens to the kidneys during the course of this disease? 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. ^^^top^^^ How will the doctor treat this disease? 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:
1. The severity of the lesions, as revealed by the biopsy; 2. The degree of proteinuria (usually proteinuria greater than 2,000 mg/day warrants treatment); 3. 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. ^^^top^^^ Should I follow a special diet? Your doctor may want to put you on a low-salt diet to minimize stress of the kidneys and prevent excess fluid retention that would strain your heart. This is especially likely if you have shown signs of edema or hypertension. Even if you are not showing such signs, a low-sodium diet may be a good idea. It won’t hurt and it may well help, particularly for those being treated with prednisone, which tens to make the body retain sodium. How strict a diet is the question. When we think "low sodium," we think of eliminating potato chips, pretzels, cocktail peanuts — all snack foods with added table salt (sodium chloride). But sodium appears in other forms, such as sodium bicarbonate (baking soda), sodium propionate (a preservative), dihydroxyaluminum sodium carbonate (antacids), sodium fluoride (toothpaste), and monosodium glutamate (m.s.g.). Whether the culprit is all forms of sodium or only table salt is not clear. Sodium chloride is naturally high in some foods, from soup to pickles to breakfast cereals. Even some frozen vegetables, such as peas and lima beans, have added salt. 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. ] ^^^top^^^ What could I be doing to help myself? This is a highly personal issue. Often patients feel frustrated because there is so little that can be done for people with IgAN, particularly in the early stages of the disease. We have actually had patients report that their doctors told them: "Come back when you need dialysis, because there is nothing I can do for you now." Needless to say, that approach doesn’t help anyone who’s suffering from a difficult and poorly understood disease! The Network suggests a number of ways you may help manage your IgAN. Not all of these will benefit everyone, because our responses to therapies, as to disease, are conditioned by individual differences. But as long as there is no medical cure for IgAN, it is worth checking out non-drug means of slowing the disease’s progression. 1. Experiment with dietary changes, as recommended above. It can be tricky to persuade teenagers to sacrifice fast food for the sake of their kidneys, but sometimes they’re willing to do a trial of a new diet for a month or two to see if it makes them feel better. 2. Avoid tobacco. Nicotine constricts the blood vessels, raising pressure and affecting peripheral circulation. People with renal disease don’t need anything that may induce higher blood pressure or impair circulation. 3. Drink plenty of pure water. If you are not absolutely sure about the purity of your municipal or private water supply, drink distilled water (available at drugstores and some supermarkets). Avoid sodas, like colas, that are high in phosphoric acid, especially if you have suffered some loss of kidney function. 4. Support your liver. To give your liver as much help as possible in its work of removing immune complexes from the body, reduce or eliminate your intake of caffeine, which is found in many sodas, cocoa, chocolate, and tea as well as coffee. Use alcohol in moderation; excessive drinking may aggravate the disease. Naturopaths also recommend use of supportive herbal therapies, such as extracts of dandelion root and/or milk thistle to help cleanse the liver. 5. Avoid medications toxic to the kidneys. This includes such painkillers as Tylenol, Advil, Motrin, etc. All of these contain either ibuprofen or acetaminophen, both of which are nephrotoxic. The same is true of most prescription painkillers. [For more information, see Headaches and Analgesics] Whenever you are treated by a doctor other than your nephrologist, be sure that doctor is aware of your IgAN and knowledgeable about not prescribing any medication or antibiotics (such as tetracycline) that might be toxic to your kidneys, either by themselves or in combination with other drugs. Toluene, either through industrial exposure or glue-sniffing, is also toxic to the kidneys. 6. Take anti-oxidants. Vitamin C and vitamin E, pycnogenol or grapeseed extract can be very helpful. Injury to the kidneys is largely caused by free radicals released as part of the body’s inflammatory response; anti-oxidants act as scavengers to remove these from the body, thereby mitigating the damage. [For other supplementation that may be helpful, particularly in more advanced disease, see Life Extension Foundation, Disease Prevention and Treatment, 4th edition (2003), "Kidney Disease," pp. 963-78.] 7. Look to alternative medicine. There is much that homeopathy, naturopathy, Chinese herbal medicine, and acupuncture can do to alleviate specific symptoms as well as retard the progress of IgAN, particularly in the early stages. It is our belief that BEFORE employing drastic medical treatments, such as the use of immunosuppressive drugs, gentler, non-toxic means should be considered. The difficulty is finding a practitioner who is skilled in treating not necessarily IgAN but other complex, chronic, immunologically-mediated conditions such as rheumatoid arthritis, fibromyalgia, chronic fatigue syndrome, and lupus. [See Links to Homeopathic Organizations for Referrals] 8. Be comfortable with your doctor. This is more difficult to achieve in these days of managed care, but be sure you are working with a nephrologist you trust, one who answers your questions fully and freely. If you have any doubts about your doctor’s competence or availability, start looking for another nephrologist. This is a long-term relationship; it should be one you feel good about. If you are not in need of dialysis and hope to avoid it in the future, you might want to steer clear of nephrologists who have a financial interest in dialysis centers. At its worst, this is a blatant conflict of interest; at best, it raises the question of whether such physicians are focused on preventing the progression of renal disease. 9. Get plenty of sleep. Most IgAN patients complain of fatigue and need more sleep than before they became ill. 10. Watch your physical activities. Exercise is a good idea, and it is rare to have any limitations put on it. But it doesn’t hurt to keep an eye on how strenuous your activities are, particularly if they seem to be inducing hematuria. 11. Test your urine. This suggestion is most likely to appeal to parents who want to monitor their children’s proteinuria and hematuria. Some patients find it reassuring to test and look for patterns in their proteinuria or hematuria; others may feel more comfortable sticking with the 24-hour urinalyses prescribed by their doctor. Chemically-treated dipsticks are available for different kinds of tests. Ames Albustix test only for urinary protein, whereas their Multistix test not only for protein but also for blood, specific gravity, pH, ketones, leukocytes, etc. The latter are expensive, but useful when it comes to checking on hematuria. Your druggist can order these for you. (Note: Dipstick tests measure only the concentration of protein in a given sample, usually the first morning void. They won’t tell you how much protein you’re losing on a given day — only a 24-hour urinalysis can do that.) 12. Avoid stresses to your immune system. Because the immune system is not operating properly in IgAN, it is important to avoid placing unnecessary stresses upon it. You should minimize your exposure to things to which you are allergic (or know you are allergic) and avoid people who have coughs and colds, especially during flu season. (This advice is hard to follow for teachers and parents with little ones.) Vaccinations are another major source of stress to the immune system; indeed, there are cases of IgAN that developed following vaccination, particularly when more than one vaccination was given or the person was vaccinated when ill, as can happen in the military. It is a good idea to avoid vaccinations that are not absolutely necessary and to avoid all multivalent vaccines. Space inoculations as far apart as possible — one week at least — and take plenty of vitamin C afterward. If your child has IgAN, talk to his or her doctor about getting an exemption from state-mandated vaccinations on grounds of health. If you are worried about contracting influenza, whooping cough, mumps, or any of the other diseases covered by vaccines, talk to a homeopath or naturopath about alternatives to vaccination. [For more information, see To Vaccinate or Not] 13. Keep in mind that IgAN is a CHRONIC disease. It’s not like a bout of bronchitis — there’s no pill that can cure it. It is not a disease that suddenly and spontaneously remits. Overcoming IgAN takes not weeks but years. You can expect to be sick much of the time, particularly in cold weather. Dealing with chronic illness requires a lot of support, for you and your family, because it is an emotionally (and financially) draining experience. Unfortunately, given IgAN’s relative rarity, you are unlikely to find a support group devoted to this disease, but you may be able, with the help of your hospital’s nephrology department, to put together a group based on kidney disorders in general. The diseases may be different, but you’ll face a lot of common problems. If you are married, your spouse may wish to join a caregivers’ support group, which some hospitals offer. Remember, too, that because IgAN is chronic, you’ll have to be followed regularly by your doctors. Even if you are asymptomatic [showing no symptoms of the disease], it is important to have periodic evaluations in accordance with your nephrologist’s recommendations. Sometimes the disease can worsen even though you are showing no overt symptoms. ^^^top^^^ What are my chances of having a remission without treatment? It is impossible to say, because this has not been well researched. While it is extremely unlikely for adults to undergo spontaneous remission, remissions do appear to occur occasionally among children. One study estimated that in perhaps 4% of reported IgAN cases there had been a spontaneous remission of all clinical symptoms. Whether this was paralleled by the spontaneous disappearance of IgA deposits in the kidneys, or by the restoration of normal glomerular structure is unknown. Patients in remission are rarely biopsied or studied to see what might have induced their remission. Some doctors believe the use of corticosteroids or other immunosuppressive medications may reduce chances for a natural remission. ^^^top^^^ What happens to those who go on to kidney failure? 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. ^^^top^^^ Will my children develop IgAN? IgAN is not a hereditary disease, like cystic fibrosis or Huntington’s chorea. In certain families, there does appear to be a predisposition to develop the disease, suggesting a genetic component. But before you can develop IgA Nephropathy, there must be some kind of trigger. We just don’t know what that is. If you are worried about your children possibly developing IgAN, make sure to have their urine tested as part of a routine physical exam. Urinary abnormalities are fairly common, so don’t assume the child has IgAN if a single test shows a problem. That’s just a signal that more thorough testing is necessary. 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). ^^^top^^^ Should a woman who has IgAN bear children? This is a tough call and one that can be made only on an individual basis, after careful consultation with your nephrologist. You may not have to worry about transmitting it to your unborn child (it’s not communicable to a fetus like AIDS), but you do have to worry about whether IgAN will affect your baby in other ways and whether pregnancy might accelerate progression of the disease in you. Studies generally agree that women who do NOT have hypertension or impaired renal function have a very good chance of producing a healthy infant, with no adverse effects to their own health. According to guidelines published by one researcher, this means that your blood pressure must consistently be under 140/90 mm Hg and your serum creatinine no more than 1.1. mg/dL (equivalent to a glomerular filtration rate of 70 ml/min or better) before you become pregnant. Hypertension may be brought on by pregnancy, but if it can be controlled by medication it should pose no threat to the fetus. Women with chronic glomerulonephritis, such as IgAN, do run a higher risk of miscarrying, of having a stillborn baby or one with low birth weight and growth retardation, and of having complications during birth, such as premature delivery or severe bleeding after delivery. One Japanese study of various kidney diseases found that 90% of the pregnancies in women with normal blood pressure were successful, whereas hypertensive women lost their babies 33% of the time. Some centers report even higher loss rates, but that may be due to having patients with more numerous complications. We have talked to women who lost as many as five pregnancies before their underlying IgAN was discovered. Women with kidney disease run a heightened risk of developing preeclampsia, a serous condition that can appear late in pregnancy and is characterized by a sudden rise in blood pressure, excessive weight gain, edema, proteinuria, terrible headaches, and visual disturbances. Preeclampsia threatens both mother and fetus. There is also the possibility that pregnancy may worsen a woman’s IgAN. Again, generally speaking, the risks are greater for a woman whose blood pressure is high or whose kidney function already impaired at the beginning of her pregnancy. There are a minority, however, who start with good clinical signs but rapidly deteriorate during pregnancy or after delivery. On their biopsies, some researchers find, these women are likely to have tubulointerstitial changes involving more than 20% of the renal cortex [outer layer of the kidney]. They may also have arteriolosclerosis [thickening of the lining of the kidney’s arterioles, which are the terminal branches of its arteries]. To assess how risky a pregnancy might be for you, you should discuss your biopsy and lab results with your nephrologist, preferably before becoming pregnant. Another factor to consider is the availability of specialized obstetrical care in your area. Women with IgAN are likely to require the services of an obstetrician who is willing and qualified to handle high-risk pregnancies. ^^^top^^^ |
