(See also Overview of Nephritic Syndrome Overview of Nephritic Syndrome Nephritic syndrome is defined by hematuria, variable degrees of proteinuria, usually dysmorphic red blood cells (RBCs), and often RBC casts on microscopic examination of urinary sediment. Often... read more .)
IgA nephropathy is a nephritic syndrome, a form of chronic glomerulonephritis Chronic glomerulonephritis Nephritic syndrome is defined by hematuria, variable degrees of proteinuria, usually dysmorphic red blood cells (RBCs), and often RBC casts on microscopic examination of urinary sediment. Often... read more characterized by the deposition of IgA immune complexes in glomeruli. It is the most common form of glomerulonephritis worldwide. It occurs at all ages, with a peak onset in the teens and 20s; affects men 2 to 6 times more frequently than women; and is more common in whites and Asians than in blacks. Prevalence estimates for IgA kidney deposits are 5% in the US, 10 to 20% in southern Europe and Australia, and 30 to 40% in Asia. However, some people with IgA deposits do not develop clinical disease.
Cause is unknown, but evidence suggests that there may be several mechanisms, including
Increased IgA1 production
Defective IgA1 glycosylation causing increased binding to mesangial cells
Decreased IgA1 clearance
A defective mucosal immune system
Overproduction of cytokines stimulating mesangial cell proliferation
Familial clustering has also been observed, suggesting genetic factors at least in some cases.
Renal function is initially normal, but symptomatic renal disease may develop. A few patients present with acute kidney injury Acute Kidney Injury (AKI) Acute kidney injury is a rapid decrease in renal function over days to weeks, causing an accumulation of nitrogenous products in the blood (azotemia) with or without reduction in amount of urine... read more or chronic kidney disease Chronic Kidney Disease Chronic kidney disease (CKD) is long-standing, progressive deterioration of renal function. Symptoms develop slowly and in advanced stages include anorexia, nausea, vomiting, stomatitis, dysgeusia... read more , severe hypertension Hypertensive Emergencies A hypertensive emergency is severe hypertension with signs of damage to target organs (primarily the brain, cardiovascular system, and kidneys). Diagnosis is by blood pressure (BP) measurement... read more , or nephrotic syndrome Overview of Nephrotic Syndrome Nephrotic syndrome is urinary excretion of > 3 g of protein/day due to a glomerular disorder plus edema and hypoalbuminemia. It is more common among children and has both primary and secondary... read more .
Symptoms and Signs
The most common manifestations are persistent or recurrent macroscopic hematuria or asymptomatic microscopic hematuria with mild proteinuria. Flank pain and low-grade fever may accompany acute episodes. Other symptoms are usually not prominent.
Gross hematuria usually begins 1 or 2 days after a febrile mucosal (upper respiratory, sinus, enteral) illness, thus mimicking acute postinfectious glomerulonephritis Postinfectious Glomerulonephritis (PIGN) Postinfectious glomerulonephritis occurs after infection, usually with a nephritogenic strain of group A beta-hemolytic streptococcus. Diagnosis is suggested by history and urinalysis and confirmed... read more , except the onset of hematuria is earlier (coinciding with or immediately after the febrile illness). When this occurs with an upper respiratory illness, it is sometimes referred to as synpharyngitic hematuria.
Rapidly progressive glomerulonephritis Rapidly Progressive Glomerulonephritis (RPGN) Rapidly progressive glomerulonephritis is acute nephritic syndrome accompanied by microscopic glomerular crescent formation with progression to renal failure within weeks to months. Diagnosis... read more is the initial manifestation in < 10% of patients.
Diagnosis is suggested by any of the following:
Gross hematuria Isolated Hematuria Hematuria is red blood cells (RBCs) in urine, specifically > 3 RBCs per high-power field on urine sediment examination. Urine may be red, bloody, or cola-colored (gross hematuria with oxidation... read more , particularly within 2 days of a febrile mucosal illness or with flank pain
Incidentally noted findings on urinalysis
Occasionally, rapidly progressive glomerulonephritis
When manifestations are moderate or severe, diagnosis is confirmed by biopsy.
Urinalysis demonstrates microscopic hematuria, usually with dysmorphic red blood cells (RBCs) and occasionally RBC casts. Mild proteinuria (< 1 g/day) is typical and may occur without hematuria; nephrotic syndrome Overview of Nephrotic Syndrome Nephrotic syndrome is urinary excretion of > 3 g of protein/day due to a glomerular disorder plus edema and hypoalbuminemia. It is more common among children and has both primary and secondary... read more develops in ≤ 20%. Serum creatinine level is usually normal.
Renal biopsy shows granular deposition of IgA and complement (C3) on immunofluorescent staining in an expanded mesangium with foci of segmental proliferative or necrotizing lesions. Importantly, mesangial IgA deposits are nonspecific and also occur in many other disorders, including immunoglobulin A–associated vasculitis Immunoglobulin A–Associated Vasculitis (IgAV) Immunoglobulin A–associated vasculitis (formerly called Henoch-Schönlein purpura) is vasculitis that affects primarily small vessels. It occurs most often in children. Common manifestations... read more , cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic fibrosis that has resulted in widespread distortion of normal hepatic architecture. Cirrhosis is characterized by regenerative nodules surrounded by dense... read more , inflammatory bowel disease Overview of Inflammatory Bowel Disease Inflammatory bowel disease (IBD), which includes Crohn disease and ulcerative colitis, is a relapsing and remitting condition characterized by chronic inflammation at various sites in the gastrointestinal... read more , celiac disease Celiac Disease Celiac disease is an immunologically mediated disease in genetically susceptible people caused by intolerance to gluten, resulting in mucosal inflammation and villous atrophy, which causes malabsorption... read more , psoriasis Psoriasis Psoriasis is an inflammatory disease that manifests most commonly as well-circumscribed, erythematous papules and plaques covered with silvery scales. Multiple factors contribute, including... read more , HIV infection Human Immunodeficiency Virus (HIV) Infection Human immunodeficiency virus (HIV) infection results from 1 of 2 similar retroviruses (HIV-1 and HIV-2) that destroy CD4+ lymphocytes and impair cell-mediated immunity, increasing risk of certain... read more , lung cancer Overview of Lung Tumors Lung tumors may be Primary Metastatic from other sites in the body Primary tumors of the lung may be Malignant (see table Classification of Primary Malignant Lung Tumors) read more , and several connective tissue disorders.
Glomerular IgA deposition is a primary feature of immunoglobulin A–associated vasculitis, and it may be indistinguishable from IgA nephropathy based on biopsy specimens, leading to speculation that immunoglobulin A–associated vasculitis may be a systemic form of IgA nephropathy. However, immunoglobulin A–associated vasculitis Immunoglobulin A–Associated Vasculitis (IgAV) Immunoglobulin A–associated vasculitis (formerly called Henoch-Schönlein purpura) is vasculitis that affects primarily small vessels. It occurs most often in children. Common manifestations... read more is clinically distinct from IgA nephropathy, usually manifesting as hematuria, purpuric rash, arthralgias, and abdominal pain.
Other serum immunologic tests are usually unnecessary. Complement concentrations are usually normal. Plasma IgA concentration may be elevated, and circulating IgA-fibronectin complexes are present; however, these findings are not helpful diagnostically.
IgA nephropathy usually progresses slowly; renal insufficiency and hypertension develop within 10 years in 15 to 20% of patients. Progression to end-stage renal disease Chronic Kidney Disease Chronic kidney disease (CKD) is long-standing, progressive deterioration of renal function. Symptoms develop slowly and in advanced stages include anorexia, nausea, vomiting, stomatitis, dysgeusia... read more occurs in 25% of patients after 20 years. When IgA nephropathy is diagnosed in childhood, prognosis is usually good. However, persistent hematuria invariably leads to hypertension, proteinuria, and renal insufficiency. Risk factors for progressive deterioration in renal function include the following:
Proteinuria > 1 g/day
Elevated serum creatinine level
Persistent microscopic hematuria
Extensive fibrotic changes in the glomerulus or interstitium
Crescents on biopsy
Often angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) for hypertension Hypertension Hypertension is sustained elevation of resting systolic blood pressure (≥ 130 mm Hg), diastolic blood pressure (≥ 80 mm Hg), or both. Hypertension with no known cause (primary; formerly, essential... read more , serum creatinine > 1.2 mg/dL (106.08 micromol/L), or macroalbuminuria (urinary protein > 300 mg/day) and with a target urinary protein of < 500 mg/day
Corticosteroids for progressive disease, including increasing proteinuria, especially into the nephrotic range, or increasing serum creatinine level
Corticosteroids and cyclophosphamide for proliferative injury or rapidly progressive glomerulonephritis Rapidly Progressive Glomerulonephritis (RPGN) Rapidly progressive glomerulonephritis is acute nephritic syndrome accompanied by microscopic glomerular crescent formation with progression to renal failure within weeks to months. Diagnosis... read more
Normotensive patients with intact renal function (serum creatinine < 1.2 mg/dL [106.08 micromol/L]) and only mild proteinuria (< 0.5 g/day) usually are not treated beyond angiotensin inhibition (with an ACE inhibitor or ARB) and omega-3 fatty acids (fish oil). Patients with renal insufficiency or more severe proteinuria and hematuria are usually offered treatment, which ideally should be started before significant renal insufficiency develops.
Angiotensin inhibition in IgA nephropathy
ACE inhibitors or ARBs are used on the premise that they reduce blood pressure, proteinuria, and glomerular fibrosis. Patients with the DD genotype for the ACE gene may be at greater risk of disease progression but may also be more likely to respond to ACE inhibitors or ARBs. For patients with hypertension, ACE inhibitors or ARBs are the antihypertensives of choice even for relatively mild chronic kidney disease.
Corticosteroids and immunosuppressants in IgA nephropathy
Corticosteroids have been used for many years, but benefit is not well documented. One protocol uses methylprednisolone 1 g IV once a day for 3 days at the beginning of months 1, 3, and 5 plus prednisone 0.5 mg/kg orally every other day for 6 months. Another regimen uses prednisone beginning 1 mg/kg orally once a day with dose gradually tapered over 6 months.
Because of the risk of adverse effects, corticosteroids should probably be reserved for patients with any of the following:
Worsening or persistent proteinuria (> 1 g/day), especially if in the nephrotic range despite maximal ACE inhibitor or ARB therapy
Increasing serum creatinine level
Combinations of IV corticosteroids and cyclophosphamide plus oral prednisone are used for severe disease, such as proliferative or crescentic (rapidly progressive) nephropathy. Evidence for mycophenolate mofetil is conflicting; it should not be used as first-line treatment. None of these drugs, however, prevents recurrence in transplant patients. Immunosuppressive therapy should also be avoided in patients with advanced fibrotic kidney disease, which is not reversible.
Omega-3 polyunsaturated fatty acids (eg, 4 to 12 g/day), available in fish oil supplements, have been used to treat IgA nephropathy, but data on efficacy are contradictory. Mechanism of effect may include alterations in inflammatory cytokines.
Other interventions have been tried to lower IgA overproduction and to inhibit mesangial proliferation. Elimination of gluten, dairy products, eggs, and meat from the diet; tonsillectomy; and immune globulin 1 g/kg IV 2 days a month for 3 months followed by immune globulin 0.35 mL/kg of 16.5% solution IM every 2 weeks for 6 months all theoretically reduce IgA production. Heparin, dipyridamole, and statins are just a few examples of in vitro mesangial cell inhibitors. Data supporting any of these interventions are limited or absent, and none can be recommended for routine treatment.
Kidney transplantation Kidney Transplantation Kidney transplantation is the most common type of solid organ transplantation. (See also Overview of Transplantation.) The primary indication for kidney transplantation is End-stage renal failure... read more is better than dialysis because of excellent long-term disease-free survival. The condition recurs in ≤ 15% of graft recipients.
IgA nephropathy is the most common cause of glomerulonephritis worldwide and is common among young adults, whites, and Asians.
Consider the diagnosis in patients with unexplained signs of glomerulonephritis, particularly when it occurs within 2 days of a febrile mucosal illness or with flank pain.
Treat patients who have creatinine > 1.2 mg/dL (106.08 micromol/L) or proteinuria > 300 mg/day with ACE inhibitors or ARBs.
Reserve corticosteroids for patients with worsening renal function or proteinuria (> 1 g/day) despite maximal ACE inhibitor or ARB treatment.
Treat patients who have proliferative injury or rapidly progressive glomerulonephritis with corticosteroids and cyclophosphamide.