IgA nephropathy (IgAN), also known as Berger's disease () (and variations), or synpharyngitic glomerulonephritis, is a disease of the kidney (or nephropathy) and the immune system; specifically it is a form of glomerulonephritis or an inflammation of the glomeruli of the kidney. Aggressive Berger's disease (a rarer form of the disease) can attack other major organs, such as the liver, skin and heart.
IgA nephropathy is the most common glomerulonephritis worldwide; the global incidence is 2.5/100,000 per year amongst adults. Aggressive Berger's disease is on the NORD list of rare diseases. Primary IgA nephropathy is characterized by deposition of the IgA antibody in the glomerulus. There are other diseases associated with glomerular IgA deposits, the most common being IgA vasculitis (formerly known as Henoch–Schönlein purpura [HSP]), which is considered by many to be a systemic form of IgA nephropathy. IgA vasculitis presents with a characteristic purpuric skin rash, arthritis, and abdominal pain, and occurs more commonly in children. HSP is associated with a more benign prognosis than IgA nephropathy. In non-aggressive IgA nephropathy, there is traditionally a slow progression to chronic kidney failure in 25–30% of cases during 20 years.
Signs and symptoms The classic presentation for the non-aggressive form (in 40–50% of the cases) is episodic hematuria, which usually starts within a day or two of a non-specific upper respiratory tract infection (hence synpharyngitic), as opposed to post-streptococcal glomerulonephritis, which occurs some time (weeks) after initial infection. With both aggressive and non-aggressive Berger's disease, loin pain can also occur. The gross hematuria may resolve after a few days, though microscopic hematuria will persist; it is, however, more common with aggressive Berger's disease for gross hematuria to persist rather than microscopic hematuria. Renal function usually remains normal with non-aggressive Berger's disease, though rarely acute kidney failure may occur (see below). This presentation is more common in younger adults.
A smaller proportion (20–30%), usually the older population, has microscopic hematuria and proteinuria (less than 2 grams/day). These patients may be asymptomatic and only picked up due to urinalysis. Hence, the disease is more commonly diagnosed in situations where screening of urine is compulsory (e.g., schoolchildren in Japan).
Very rarely (5% each), the presenting history is: Nephritic syndrome Acute kidney failure (either as a complication of the frank hematuria, when it usually recovers, or due to rapidly progressive glomerulonephritis which often leads to chronic kidney failure) Chronic kidney failure (no previous symptoms, presents with anemia, hypertension, and other symptoms of kidney failure, in people who probably had longstanding undetected microscopic hematuria and/or proteinuria)
A variety of systemic diseases are associated with aggressive IgA nephropathy (Berger's disease) such as liver failure, cancer, celiac disease, systemic lupus erythematosus, rheumatoid arthritis, heart failure, reactive arthritis, ankylosing spondylitis and HIV. Diagnosis of Berger's disease and a search for any associated disease occasionally reveals an underlying serious systemic disease. Occasionally, there are simultaneous symptoms of Henoch–Schönlein purpura; see below for more details on the association. Some HLA alleles have been suspected, along with complement phenotypes, as being genetic factors. Non-aggressive Berger's disease may also be associated with any of the above systemic diseases; however, this is rare.
Morphology Histologically, IgA nephropathy may show mesangial widening and focal and segmental inflammation. Diffuse mesangial proliferation or crescentic glomerulonephritis may also be present. Immunofluorescence shows mesangial deposition of IgA often with C3 and properdin and smaller amounts of other immunoglobulins (IgG or IgM). Early components of the classical complement pathway (C1q or C4) are usually not seen. Electron microscopy confirms electron-dense deposits in the mesangium that may extend to the subendothelial area of adjacent capillary walls in a small subset of cases, usually those with focal proliferation.
Pathophysiology
The disease derives its name from deposits of immunoglobulin A (IgA) in a granular pattern in the mesangium (by immunofluorescence), a region of the renal glomerulus. The mesangium by light microscopy may be hypercellular and show increased deposition of extracellular matrix proteins. In terms of the renal manifestation of Henoch–Schönlein purpura, it has been found that although it shares the same histological spectrum as IgA nephropathy, a greater frequency of severe lesions such as glomerular necrosis and crescents was observed. Correspondingly, HSP nephritis has a higher frequency of glomerular staining for fibrin compared with IgAN, but with an otherwise similar immunofluorescence profile.
There is no clear known explanation for the accumulation of IgA. Exogenous antigens for IgA have not been identified in the kidney, but this antigen may have been cleared before the disease manifests itself. It has also been proposed that IgA itself may be the antigen.
Gd-IgA1
A recently advanced theory focuses on post-translational abnormalities of the IgA1 molecule of the Type III hypersensitivity type. IgA1 is one of the two immunoglobulin subclasses (the other is IgD) that is O-glycosylated on many serine and threonine residues in a special proline-rich hinge region.
Under-galactosylated IgA1 antibodies bind with IgG antibodies in the blood, and that such IgA1-IgG complexes get deposited in the kidneys, especially the glomerular mesangium, as happens in type III hypersensitivity disorders. This is followed by inflammation and hematuria.
A similar mechanism has been claimed to underlie Henoch–Schönlein purpura, a vasculitis that mainly affects children and can feature renal involvement that is almost indistinguishable from IgA nephritis. However, human studies have found that degalactosylation of IgA1 occurs in patients with IgA nephropathy in response only to gut antigen exposures (not systemic), and occurs in healthy people to a lesser extent. This strongly suggests degalactosylation of IgA1 is a result of an underlying phenomenon (abnormal mucosal antigen handling) and not the ultimate cause of IgA nephropathy. Prevailing evidence suggests that both galactose-deficient o-glycans in the hinge region of IgA1 and the synthesis and binding of antibodies against IgA1 are required for immunoglobulin complexes to form and accumulate in glomeruli.
From the fact that IgAN can recur after renal transplant, it can be postulated that the disease is caused by a problem in the immune system rather than the kidney itself. Remarkably, the IgA1 that accumulates in the kidney does not appear to originate from the mucosa-associated lymphoid tissue (MALT), which is the site of most upper respiratory tract infections, but from the bone marrow. This, too, suggests an immune pathology rather than direct interference by outside agents.
Prognosis Since IgA nephropathy commonly presents without symptoms through abnormal findings on urinalysis, there is considerable possibility for variation in any population studied, depending upon the screening policy. Similarly, the local policy for performing kidney biopsy assumes a critical role; if it is a policy to simply observe patients with isolated bloody urine, a group with a generally favourable prognosis will be excluded. If, in contrast, all such patients are biopsied, then the group with isolated microscopic hematuria and isolated mesangial IgA will be included and improve the prognosis of that particular series.
Nevertheless, IgA nephropathy, which was initially thought to be a benign disease, is not a benign condition, particularly if the patient presents with an aggressive form. Though most reports describe Berger's disease as having an indolent evolution towards either healing or renal damage, a more aggressive course is occasionally seen associated with extensive crescents, and presenting as acute kidney failure. In general, the entry into chronic kidney failure is slow as compared to most other glomerulonephritides – occurring over a time scale of 30 years or more (in contrast to the 5 to 15 years in other glomerulonephritides), however, in aggressive Berger's disease the time scale is within 5–10 years and often sooner. This may reflect the earlier diagnosis made due to frank hematuria.
Complete remission of aggressive Berger's disease rarely occurs in adults. In about 5% of cases, however, there is a higher chance of remission with non-aggressive Berger's disease (this is estimated to be around 7.4% of cases). There is a high chance of relapse, particularly with aggressive Berger's disease. However, given the evolution of this disease, the longer-term (10–20 years) outcome of such patients is not yet established.
Overall, the current 10-year survival rate for aggressive Berger's disease is 25% and 73% for non-aggressive Berger's disease.
Genetic and Environmental Influences on IgA Nephropathy
IgA nephropathy (IgAN) is primarily a sporadic disease, with over 90% of cases classified as such. However, recent findings have uncovered a significant genetic component that influences both the regulation of serum IgA levels and susceptibility to the disease. Research has demonstrated positive associations between genetic regulation of IgA and conditions such as IgAN and type 2 diabetes, whereas negative associations have been observed with celiac disease and inflammatory bowel disease. Notably, a study conducted by Liu et al. highlighted ancestral differences, revealing that individuals of African descent consistently have higher serum IgA levels. These findings suggest a complex interplay of genetic factors in regulating IgA levels and contributing to the susceptibility of various immune, kidney, and metabolic disorders.
Another study utilized a two-sample Mendelian randomization approach to explore causal relationships between IgAN and several factors, including neuropsychiatric disorders and dietary intake. The study found a positive causal link between IgAN and depressive disorders, as well as a potential link with anorexia nervosa. However, no causal relationships were identified with schizophrenia, bipolar disorder, or Alzheimer's disease. This indicates that IgAN may share genetic or biological pathways specifically with certain neuropsychiatric conditions, potentially influencing their development.
Diagnosis For an adult patient with isolated hematuria, tests such as ultrasound of the kidney and cystoscopy are usually done first to pinpoint the source of the bleeding. These tests would rule out kidney stones and bladder cancer, two other common urological causes of hematuria. In children and younger adults, the history and association with respiratory infection can raise the suspicion of IgA nephropathy. A kidney biopsy is necessary to confirm the diagnosis. The biopsy specimen shows proliferation of the mesangium, with IgA deposits on immunofluorescence and electron microscopy. However, patients with isolated microscopic hematuria (i.e., without associated proteinuria and with normal kidney function) are not usually biopsied since this is associated with an excellent prognosis. A urinalysis will show red blood cells, usually as red cell urinary casts. Proteinuria, usually less than 2 grams per day, also may be present. Other renal causes of isolated hematuria include thin basement membrane disease and Alport syndrome, the latter being a hereditary disease associated with hearing impairment and eye problems.
Other blood tests done to aid in the diagnosis include CRP or ESR, complement levels, ANA, and LDH. Protein electrophoresis and immunoglobulin levels can show increased IgA in 50% of all patients.
Treatment