bubble_chart Overview

IgA nephritis (IgA glomerulonephritis) is a primary glomerular disease characterized by recurrent episodes of gross or microscopic hematuria, proliferation of mesangial cells in the glomeruli, increased matrix, and extensive IgA deposition. First described by Berger in 1968, it is also known as Berger's disease. Additionally, it is referred to as IgA-IgG mesangial deposition nephritis and IgA mesangial nephritis.

bubble_chart Epidemiology

There are significant differences in the reported incidence rates worldwide, with the Western Pacific region appearing to have the highest rates. Japan reports that it accounts for 50% of biopsy-confirmed glomerular diseases, while Europe reports about 10–30%, and the United States less than 2%. Reports from various regions in China also vary, generally around 20–30%. These differences are clearly influenced by the indications for renal biopsy and urine screening practices in different regions. For example, the UK generally reports around 5%, whereas in Scotland, biopsies of asymptomatic hematuria cases reached 37%. The disease is more common in males, with a male-to-female ratio of about 2:1. Racial differences exist; for instance, among Native Americans in New Mexico, USA, the incidence is 35%, whereas it is very rare among Black individuals. Although it has been found that Black individuals have significantly lower IgA₂m (1) levels compared to Caucasians, no definitive link has been established between this and the lower incidence rate. Since 1978, some reports have suggested a familial clustering tendency, indicating that at least in some individuals with IgA nephropathy, there may be a genetic predisposition. HLA analysis has revealed associations with Bw₃₅

and DR4. A recent analysis of end-stage renal failure cases caused by IgA showed an increased frequency of B₂₇ and DR1, while the frequency of DR2 decreased.

bubble_chart Pathogenesis

The pathogenesis of this disease remains unclear. Since IgA deposits can be detected in both the skin and liver of patients, it suggests a systemic disease. The presence of granular IgA and C₃ deposits in the glomerular mesangial areas and capillaries indicates an immune complex-mediated pathogenesis. Current research focuses on the ability of antigens to cross mucosal barriers, potential defects in these barriers, structural abnormalities of IgA, and possible immune regulatory dysfunctions. Earlier studies suggested that the deposited IgA might be of mucosal origin. However, recent studies using highly specific techniques have confirmed that the deposited IgA in this disease is primarily IgA₁, which is mainly systemic in origin and produced by the bone marrow and lymphatic system. Mucosal-origin IgA₂ is predominantly found in the IgA deposits of hepatic glomerulosclerosis. Elevated levels of total IgA₁ and IgA₁-containing immune complexes are also observed in the circulation of these patients, along with an increase in IgA₁-producing plasma cells in the bone marrow, predominantly forming polymers. In the renal tissue of these patients, the presence of J-chain suggests that the deposited IgA is polymeric, while secretory components are rarely found. Nevertheless, existing data cannot definitively determine the origin of the IgA deposits in this disease.

Various antigens, including those from multiple viruses and foods, have been detected in the mesangial areas of patients, often accompanied by IgA₁

deposits. The antibodies to these antigens are also of the IgA₁ type. Since these antibodies can also be present in the circulation of healthy individuals, the aforementioned antigens lack specificity or distinctiveness.

Evidence suggests abnormal immune regulation in this disease. The IgA₁ circulating immune complexes in this disease have been found to contain polymeric IgA₁ class wind-dampness factors; IgG antibodies against the Fab fragment of the α-heavy chain are increased, while IgM antibodies are decreased. Interestingly, HIV-infected individuals exhibit a similar anti-immunoglobulin pattern but do not develop renal IgA deposition. This indicates that the mere presence of these circulating autoantibodies is not the cause of membrane IgA deposition. Additionally, two types of anti-endothelial cell autoantibodies (IgG class) have been identified. Renal tissues in this disease often show C₃ deposition, suggesting activation of the complement alternative pathway. However, IgA itself cannot activate complement, and although IgA immune complexes can activate the alternative pathway, their ability to bind complement and C₃b is weak. It is generally believed that complement activation and membrane attack complex formation in the kidneys require IgG-IgA complexes, yet renal tissues in this disease frequently exhibit IgA and C₃ deposition without IgG or IgM deposition. Therefore, the mechanism of complement activation in this disease remains unclear. Cellular immunity also participates in the mechanism of disease pathogenesis. Increased T-helper cells (CD4) and decreased T-suppressor cells (CD8) have been observed in this disease. There is an increase in Ta4 cells, which switch IgM synthesis to IgA synthesis, along with an increased frequency of the associated Sa1 allele. Additionally, elevated levels of TGFβ (which induces IgA isotype switching), IL-5 (which promotes IgA-producing B lymphocyte differentiation), and IL-4 (which mediates IgA production) have been noted. Although both T cells and B cells are involved in the increased IgA synthesis, this alone does not explain membrane IgA deposition, as tissue IgA deposition is rare in IgA multiple myeloma. Thus, structural-immunological/physicochemical abnormalities are likely the cause of membrane IgA deposition.

Anti-bovine serum albumin polyclonal idiotypic antibodies can be detected in the serum and mesangium of patients with this disease, and their titers are correlated with hematuria. Recently, five monoclonal anti-idiotypic antibodies were obtained from IgA extracted from the renal cortex and glomeruli of patients. These antibodies showed poor reactivity with patient serum or plasma cells but had high reactivity with renal tissues, suggesting that renal deposition is related to the abnormal properties of these polyclonal IgA antibodies. Additionally, a deficiency of β1,1-galactosyltransferase was found in the philtrum of these patients, which alters the clearance rate of IgA₁ or IgA₁-containing complexes, leading to the deposition of IgA₁ in the mesangial region.

In summary, the deposition of antigens, with or without cell-mediated immune responses, the rate of IgA complex formation, and the clearance efficiency of mesangial cells or neutrophils with IgA Fc receptors are all involved in the overall pathogenesis of the disease. Meanwhile, cytokines and growth factors primarily participate in the mechanisms of mesangial proliferation and sclerosis.

bubble_chart Pathological Changes

The typical pathological manifestations of this disease under light microscopy commonly include mesangial cell proliferation and increased matrix, often presenting with focal and segmental distribution. In mild cases, there may only be slight mesangial proliferation, which can also appear as diffuse proliferation (often with focal and segmental exacerbation). Approximately 20% of cases may exhibit crescent formation, usually involving no more than 30% of the glomeruli. If crescents affect over 50% of the glomeruli, it is classified as rapidly progressive IgA nephropathy. Under immunofluorescence microscopy, diffusely distributed granular or lumpy IgA deposits (primarily IgA1) can be observed in the glomerular mesangium. About 60–90% of cases are accompanied by C3 and IgG deposits, though their intensity is weaker. Reports on IgM deposits vary. IgA light chains are predominantly λ-type, with J chains present but no secretory component. Typically, there are no C1q or C3 deposits. Under electron microscopy, fine, uniform granular electron-dense deposits are almost always visible in the mesangial region; if subepithelial or subendothelial deposits are present, the condition is often severe. The foot processes of epithelial cells are usually normal. In progressive cases, deformation and fragmentation of the glomerular basement membrane may be observed, along with "dissolution" of the glomerular basement membrane. The classification criteria accepted by the World Health Organization are appended at the end.

bubble_chart Clinical Manifestations

Typical cases often present with gross hematuria within hours to 2 days after an upper respiratory tract infection, usually lasting for hours to days, and in some cases up to 1 week. Such patients account for approximately 40–50% of the total, slightly higher in children. A few may experience severe lumbago and abdominal pain, possibly related to intestinal IgA vasculitis. Another common manifestation of this disease is asymptomatic hematuria and/or proteinuria, accounting for about 30–40% of cases. Among these, 20–25% may experience one or several episodes of gross hematuria during the course of the disease.

Nephrotic syndrome is observed in 5–20% of cases, more commonly in children and young adults, often presenting as diffuse proliferative type with or without glomerulosclerosis. Additionally, in some cases, predominant mesangial IgA deposition may also occur in minimal change nephropathy characterized by foot process effacement.

Less than 10% of patients may exhibit acute renal failure, which usually resolves spontaneously. Among these, 20–25% may require dialysis, mostly due to crescentic glomerulonephritis. Azotemia during the active phase of the disease is not uncommon, occurring in about 25% of cases. Hypertension is present at onset in approximately 10% of cases, but increases significantly in those diagnosed after the age of 30; with disease progression, over 40% of patients develop hypertension.

bubble_chart Auxiliary Examination

Under the microscope, hematuria is primarily characterized by deformed red blood cells in the urine. Approximately 50% of patients exhibit elevated serum IgA levels, but this is unrelated to disease activity. The concentration of λ light chains in serum IgA is increased. Urinary immunoglobulin measurements hold no special significance. Most blood complement components remain normal. Certain complement components or factors may decrease, mainly observed in patients with a familial predisposition to the disease philtrum, but this has no diagnostic value. About half of the patients may show transiently elevated levels of IgA-fibronectin aggregates, which, although helpful in differentiating from other kidney diseases, are unrelated to disease activity and thus lack diagnostic value. 10–15% of patients may have elevated IgA circulating immune complexes, while 32% exhibit increased levels of IgA-class wind-dampness factors. Multiple immunological indicators, including viral and food antigens, antibodies, T-cell subsets, and HLA locus antigens, may show alterations, but none have diagnostic significance. In 50% of patients, skin biopsies from the volar side of the forearm reveal deposits of IgA and C₃ within capillaries.

bubble_chart Diagnosis

The diagnosis of this disease must be confirmed by renal biopsy. However, many diseases exhibit significant IgA deposition in the glomerular mesangial region, necessitating careful differentiation. The most common conditions requiring differential diagnosis include: Henoch-Schönlein purpura and purpuric nephritis, systemic lupus erythematosus, and hepatic glomerulosclerosis. Additionally, collagen diseases such as ankylosing spondylitis, rheumatoid arthritis, mixed connective tissue disease, and post-infectious arthritis should be considered; intestinal disorders like celiac disease, ulcerative colitis, and regional enteritis; skin diseases such as dermatitis herpetiformis and psoriasis; tumor-related conditions including lung cancer, laryngeal carcinoma, mucinous adenocarcinoma, IgA gammopathy, mycosis fungoides, and non-Hodgkin lymphoma; hematologic disorders like cyclic neutropenia, mixed cryoglobulinemia, immune thrombocytopenia, and polycythemia; as well as idiopathic pulmonary hemosiderosis, sarcoidosis, retroperitoneal fibrosis, amyloidosis, myasthenia gravis, leprosy, HIV infection, and thin basement membrane nephropathy should also be included in the differential diagnosis.

bubble_chart Treatment Measures

To date, there is no satisfactory treatment regimen for this disease. The results of using adrenal corticosteroids with or without immunosuppressants in patients with progressive renal function decline are inconsistent. Recent data suggest that for patients with proteinuria exceeding 1g/d, alternate-day administration of adrenal corticosteroids may benefit proteinuria improvement. For minimal change nephropathy with IgA deposition, proteinuria may potentially be alleviated. Combined use of cyclophosphamide, dipyridamole, and warfarin can reduce proteinuria without affecting glomerular filtration rate; combined use of cyclosporine A can also reduce proteinuria but may decrease creatinine clearance. The efficacy of phenytoin, antiplatelet drugs, disodium cromoglycate, and diphenylhydantoin remains uncertain. Although there are reports that urokinase may have a protective effect on glomerular filtration rate, it is far from conclusive. For recurrent tonsillitis, tonsillectomy may be beneficial; antibiotic prophylaxis and treatment of infections may help some patients presenting with acute nephritic syndrome and acute kidney failure. A small series of observations found that fish oil preparations can reduce proteinuria and increase glomerular filtration rate. In severe IgA nephropathy (with glomerular filtration rate declining by 2–4 ml/min per month), high-dose intravenous immunoglobulin infusion can halt the decline in glomerular filtration rate and improve hematuria and proteinuria, but relapse often occurs after discontinuation. For cases with hypertension and grade III proteinuria, angiotensin-converting enzyme inhibitors can slow the decline in glomerular filtration rate and reduce proteinuria, making them the preferred antihypertensive for severe IgA nephropathy. Whether these inhibitors are effective in normotensive patients remains unclear.

In end-stage IgA nephropathy patients receiving kidney transplants, IgA deposits in the mesangial region of the transplanted kidney often recur quickly. If the donor has subclinical IgA nephropathy, the IgA deposits in the mesangial region of the transplanted kidney often disappear rapidly after transplantation into a non-IgA nephropathy uremic patient. Recurrent IgA nephropathy in the transplanted kidney does not necessarily lead to progressive renal failure, but post-transplant immunosuppressive therapy, including cyclosporine A, does not prevent its progression. For cadaveric kidney transplants, the 1-year and 3-year graft survival rates can reach 87% and 77%, respectively. However, in individual IgA nephropathy transplant recipients with anti-HLA antigen IgA antibodies, the 2-year graft survival rate can reach 100%, reasonably suggesting that these anti-HLA antigen antibodies play a beneficial role in increasing graft survival rates.

bubble_chart Prognosis

The disease may have spontaneous remission, accounting for about 4-20%. Approximately 1-2% of cases progress to end-stage renal failure each year. Life table statistical analysis shows a 10-year renal survival rate of 80-90%. It is estimated that about 35% of patients eventually develop uremia, while the rest exhibit persistent hematuria or proteinuria. Factors indicating a poor prognosis include renal insufficiency at onset, proteinuria exceeding 1.5g/d, hypertension, and absence of gross hematuria; renal biopsy findings such as glomerulosclerosis, interstitial fibrosis, glomerular capillary invasion, diffuse proliferation, and diffuse crescent formation.