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IgA nephropathy ( IgAN), also known as Berger's disease () (and variations), or synpharyngitic glomerulonephritis, is a kidney disease (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 purpura 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.
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:
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.
There is no clear known explanation for the accumulation of IgA. Exogenous 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.
A recently advanced theory focuses on abnormalities of the IgA1 molecule. IgA1 is one of the two immunoglobulin subclasses (the other is IgD) that is glycosylation on many serine and threonine residues in a special proline-rich hinge region. Aberrant glycosylation of IgA appears to lead to of the IgA molecules in tissues, especially the glomerular mesangium. 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.
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 (2022) 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 (TSMR) approach to explore causal relationships between IgAN and several factors, including neuropsychiatric disorders and dietary intake (Lin, 2025). 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 (Li, 2024).
The role of dietary habits in the development of IgAN was also explored using genetic data (Hernán, 2029). The study found that frequent alcohol consumption was associated with an increased risk of developing IgAN, whereas the consumption of cheese, cereal, and sushi appeared to reduce the risk. These findings suggest that diet is a modifiable factor that could potentially influence IgAN development.
Overall, these studies highlight the intricate relationship between genetics, diet, and IgAN, with potential implications for both mental health and dietary practices. Further research is needed to confirm these associations and understand the underlying mechanisms, which could inform prevention strategies for individuals at risk of IgAN. Early prevention efforts should target both genetic and lifestyle factors. Screening individuals with a family history of IgAN or related autoimmune disorders could help identify those at greater risk. Moreover, adopting a healthy diet that limits alcohol and includes protective foods such as cheese, cereal, and sushi may reduce the likelihood of developing IgAN. Early intervention through lifestyle modifications, regular monitoring of kidney function, and stress management may also help reduce the onset of neuropsychiatric conditions linked to IgAN, such as depression.
Other done to aid in the diagnosis include CRP or ESR, complement levels, ANA, and LDH. Protein electrophoresis and antibody levels can show increased IgA in 50% of all patients.
In cases where tonsillitis is the precipitating factor for episodic hematuria, a tonsillectomy has been claimed to reduce the frequency of those episodes. However, it does not reduce the incidence of progressive kidney failure. Dietary gluten restriction, used to reduce mucosal antigen challenge, also has not been shown to preserve Renal function. Phenytoin has also been tried without any benefit.
A subset of IgA nephropathy patients, who have minimal change disease on light microscopy and clinically have nephrotic syndrome, show an exquisite response to , behaving more or less like minimal change disease. In other patients, the evidence for steroids is not compelling. Short courses of high-dose steroids have been proven to lack benefit. However, in patients with aggressive Berger's disease, a 6-month regimen of steroids in addition to other medications may lessen proteinuria and preserve renal function. The study had 10 years of patient follow-up data, and did show a benefit for steroid therapy; there was a lower chance of reaching end-stage renal disease (renal function so poor that dialysis was required) in the steroid group. Importantly, angiotensin-converting enzyme inhibitors were used in both groups equally.
Cyclophosphamide (traded as endoxan and cytoxan) and Isotretinoin have commonly been used, often with anti-platelet/ in patients with Aggressive Berger's disease, however, the side effect profile of these drugs, including long term risk of malignancy and infertility, made them an unfavorable choice for use in young adults. However, one recent study, in a carefully selected high risk population of patients with declining GFR, showed that a combination of steroids and cyclophosphamide for the initial 3 months followed by azathioprine for a minimum of 2 years resulted in a significant preservation of renal function. Other agents such as mycophenolate mofetil, ciclosporin and mizoribine have also been tried with varying results.
A 1994 study by Mayo Clinic found that long-term treatment with omega−3 fatty acid-rich fish oil, which does not have the drawbacks of immunosuppressive therapy, was associated with slight reduction of progression to kidney failure, without, however, reducing proteinuria in a subset of patients with high risk of worsening kidney function. However, these results were not reproduced by other study groups and in two subsequent meta-analyses.
The events that tend to lead to progressive kidney failure are not unique to IgA nephropathy, and non-specific measures to reduce the same would be equally useful. These include a low-protein diet and optimal control of blood pressure. The choice of antihypertensive agent is open as long as the blood pressure is controlled to the desired level. However, angiotensin converting enzyme inhibitors and angiotensin II receptor antagonists are favoured due to their anti-proteinuric effect.
In December 2021, budesonide (Tarpeyo) was approved for medical use in the US to reduce proteinuria in adults with primary IgA nephropathy at risk of rapid disease progression.
Sparsentan is a therapy recently approved in the USA for treating primary IgA nephropathy. It is a dual endothelin angiotensin receptor antagonist that uniquely combines angiotensin and endothelin inhibition without immunosuppression. In clinical trials, sparsentan demonstrated significant reductions in proteinuria and better preservation of kidney function than irbesartan, a standard treatment. These results were evident in the 36-week interim analysis of the phase 3 PROTECT trial and sustained through 110 weeks in the final analysis. This approval marks a significant milestone in managing IgA nephropathy, offering new option for affected patients.
Certain other features found by kidney biopsy, such as interstitial scarring, are associated with a poor prognosis. ACE gene polymorphism has recently been shown to have an impact, with the DD genotype associated more commonly with progression to kidney failure.
Disease progression in IgAN can be predicted at the time of Renal biopsy by a risk-prediction tool.
In 1968, Jean Berger (1930–2011), a pioneering French nephrologist, with co-author electron microscopist Nicole Hinglais, was the first to describe IgA deposition in this form of glomerulonephritis and it is consequently sometimes called Berger's disease.
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