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Immunoglobulin A Nephropathy (IgA Nephropathy)
IgA nephropathy is deposition of IgA immune complexes in glomeruli, manifesting as slowly progressive hematuria, proteinuria, and, often, renal insufficiency. Diagnosis is based on urinalysis and renal biopsy. Prognosis is generally good. Treatment options include ACE inhibitors, angiotensin II receptor blockers, corticosteroids, immunosuppressants, and ω-3 polyunsaturated fatty acids.
IgA nephropathy is a nephritic syndrome, a form of chronic glomerulonephritis (GN—see Overview of Nephritic Syndrome) characterized by the deposition of IgA immune complexes in glomeruli. It is the most common form of GN 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, and 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 or chronic kidney disease, severe hypertension, or nephrotic syndrome.
The most common manifestation is persistent or recurrent macroscopic hematuria (90% of affected children) or asymptomatic microscopic hematuria with mild proteinuria. 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 GN, except the onset of hematuria is earlier (coinciding with or immediately after the febrile illness). Rapidly progressive GN is the initial manifestation in < 10% of patients.
Diagnosis is suggested by any of the following:
When manifestations are moderate or severe, diagnosis is confirmed by biopsy.
Urinalysis demonstrates microscopic hematuria, usually with dysmorphic RBCs and RBC casts. Mild proteinuria (< 1 g/day) is typical and may occur without hematuria; nephrotic syndrome 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 (Henoch-Schönlein purpura), cirrhosis, inflammatory bowel disease, psoriasis, HIV infection, lung cancer, and several connective tissue disorders. Glomerular IgA deposition is a primary feature of Henoch-Schönlein purpura, and the 2 disorders may be indistinguishable 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 is clinically distinct from IgA nephropathy, usually manifesting as hematuria, purpuric rash, arthralgias, and abdominal pain (see Immunoglobulin A–Associated Vasculitis (IgAV)).
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 yr in 15 to 20% of patients. Progression to end-stage renal disease occurs in 25% of patients after 20 yr. 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:
Often ACE inhibitors or angiotensin II receptor blockers for hypertension, serum creatinine > 1.2 mg/dL, or macroalbuminuria (urinary protein > 300mg/day) and with a target urinary protein of < 500 mg/day.
Corticosteroids and possibly immunosuppressants for progressive disease, including increasing proteinuria especially into the nephrotic range, or increasing serum creatinine level
Transplantation rather than dialysis if possible
Normotensive patients with intact renal function (serum creatinine < 1.2 mg/dL) and only mild proteinuria (< 0.5 g/day) usually are not treated. Patients with renal insufficiency or more severe proteinuria and hematuria are usually offered treatment, which ideally should be started before significant renal insufficiency develops.
ACE inhibitors or angiotensin II receptor blockers are used on the premise that they reduce BP, 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 angiotensin II receptor blockers. For patients with hypertension, ACE inhibitors or angiotensin II receptor blockers are the antihypertensives of choice even for relatively mild chronic kidney disease.
Corticosteroids have been used for many years, but benefit is not well documented. One protocol uses methylprednisolone 1 g IV once/day for 3 days at the beginning of months 1, 3, and 5 plus prednisone 0.5 mg/kg po every other day for 6 mo. Another regimen uses prednisone beginning 1 mg/kg po once/day with dose gradually tapered over 6 mo. Because of the risk of adverse effects, corticosteroids should probably be reserved for patients with any of the following:
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.
ω-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/mo for 3 mo followed by immune globulin 0.35 mL/kg of 16.5% solution IM q 2 wk for 6 mo 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.
Renal transplantation 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 GN worldwide and is common among young adults, whites, and Asians.
Consider the diagnosis in patients with unexplained signs of GN, 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 or proteinuria > 300 mg/day with ACE inhibitors or angiotensin II blockers.
Treat patients with increasing creatinine level or proteinuria with corticosteroids and possibly cyclophosphamide.
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