IgA nephropathy | |
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Other names | IgA nephritis, Berger's disease |
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Immunoglobulin Adimer | |
Specialty | Nephrology Rheumatology |
IgA nephropathy (IgAN), also known asBerger's disease (/bɛərˈʒeɪ/) (and variations), orsynpharyngitic glomerulonephritis, is adisease of the kidney (or nephropathy) and theimmune system; specifically it is a form ofglomerulonephritis or aninflammation of theglomeruli of thekidney. Aggressive Berger's disease (a rarer form of the disease) can attack other major organs, such as theliver,skin andheart.
IgA nephropathy is the most common glomerulonephritis worldwide; the global incidence is 2.5/100,000 per year amongst adults.[1] Aggressive Berger's disease is on theNORD list of rare diseases.[2] Primary IgA nephropathy is characterized by deposition of theIgAantibody in the glomerulus. There are other diseases associated with glomerular IgA deposits, the most common beingIgA vasculitis (formerly known asHenoch–Schönlein purpura [HSP]), which is considered by many to be a systemic form of IgA nephropathy.[3] IgA vasculitis presents with a characteristicpurpuric 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 a period of 20 years.
The classic presentation for the non-aggressive form (in 40–50% of the cases) is episodichematuria, which usually starts within a day or two of a non-specificupper respiratory tract infection (hencesynpharyngitic), as opposed topost-streptococcal glomerulonephritis, which occurs some time (weeks) after initial infection. With both aggressive and non-aggressive Berger's diseaseloin pain can also occur. The gross hematuria may resolve after a few days, thoughmicroscopic 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 rarelyacute kidney failure may occur (see below). This presentation is more common in younger adults.[citation needed]
A smaller proportion (20–30%), usually the older population, have microscopic hematuria andproteinuria (less than 2 gram/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 inJapan).[citation needed]
Very rarely (5% each), the presenting history is:[citation needed]
A variety of systemic diseases are associated with aggressive IgA nephropathy (Berger's disease) such asliver failure,cancer,celiac disease,systemic lupus erythematosus,rheumatoid arthritis,heart failure,reactive arthritis,ankylosing spondylitis andHIV. Diagnosis of Berger's disease and a search for any associated disease occasionally reveals such an underlying serious systemic disease. Occasionally, there are simultaneous symptoms ofHenoch–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.[citation needed]
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 withC3 andproperdin and smaller amounts of other immunoglobulins (IgG orIgM). Early components of theclassical complement pathway (C1q orC4) 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.[citation needed]
The disease derives its name from deposits ofimmunoglobulin A (IgA) in a granular pattern in the mesangium (byimmunofluorescence), a region of the renalglomerulus. The mesangium by light microscopy may be hypercellular and show increased deposition ofextracellular matrix proteins. In terms of the renal manifestation ofHenoch–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 were observed. Correspondingly, HSP nephritis has a higher frequency of glomerular staining for fibrin compared with IgAN, but with an otherwise similar immunofluorescence profile.[4]
There is no clear known explanation for the accumulation of the IgA. Exogenousantigens for IgA have not been identified in the kidney, but it is possible that this antigen has been cleared before the disease manifests itself. It has also been proposed that IgA itself may be the antigen.[citation needed]
A recently advanced theory focuses on abnormalities of the IgA1 molecule. IgA1 is one of the two immunoglobulin subclasses (the other is IgD) that isO-glycosylated on a number ofserine andthreonine residues in a specialproline-rich hinge region. Aberrant glycosylation of IgA appears to lead topolymerisation of the IgA molecules in tissues, especially the glomerular mesangium.[5] A similar mechanism has been claimed to underlieHenoch–Schönlein purpura, avasculitis 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.[6] 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 synthesis and binding of antibodies against IgA1 are required for immunoglobulin complexes to form and accumulate in glomeruli.[7]
From the fact that IgAN can recur after renal transplant, it can be postulated that the disease is caused by a problem in theimmune 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 thebone marrow. This, too, suggests an immune pathology rather than direct interference by outside agents.[8][9]
Since IgA nephropathy commonly presents without symptoms through abnormal findings onurinalysis, there is considerable possibility for variation in any population studied depending upon thescreening policy. Similarly, the local policy for performing kidneybiopsy assumes a critical role; if it is a policy to simply observe patients with isolatedbloody urine, a group with a generally favourableprognosis will be excluded. If, in contrast, all such patients are biopsied, then the group with isolatedmicroscopic hematuria and isolated mesangial IgA will be included and improve the prognosis of that particular series.[citation needed]
Nevertheless, IgA nephropathy, which was initially thought to be a benign disease, has been shown to not be a benign disease, 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 asacute kidney failure. In general, the entry intochronic 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.[citation needed]
Completeremission 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.[citation needed]
Overall, the current 10-year survival rate for aggressive Berger's disease is 25% and 73% for non-aggressive Berger's disease.[citation needed]
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.
For an adult patient with isolatedhematuria, tests such asultrasound of the kidney andcystoscopy are usually done first to pinpoint the source of thebleeding. These tests would rule outkidney stones andbladder cancer, two other commonurological causes of hematuria. In children and younger adults, the history and association with respiratory infection can raise the suspicion of IgA nephropathy. A kidneybiopsy is necessary to confirm the diagnosis. The biopsy specimen shows proliferation of themesangium, with IgA deposits onimmunofluorescence andelectron microscopy. However, patients with isolatedmicroscopic hematuria (i.e. without associated proteinuria and with normalkidney function) are not usually biopsied since this is associated with an excellentprognosis. Aurinalysis will showred blood cells, usually as red cellurinary casts.Proteinuria, usually less than 2 grams per day, also may be present. Otherrenal causes of isolated hematuria includethin basement membrane disease andAlport syndrome, the latter being ahereditary disease associated withhearing impairment and eye problems.[citation needed]
Otherblood tests done to aid in the diagnosis includeCRP orESR,complement levels,ANA, andLDH.Protein electrophoresis andimmunoglobulin levels can show increased IgA in 50% of all patients.[citation needed]
The ideal treatment for IgAN would remove IgA from the glomerulus and prevent further IgA deposition. This goal still remains a remote prospect. There are a few additional caveats that have to be considered while treating IgA nephropathy. IgA nephropathy has a very variable course, ranging from a benign recurrenthematuria up to a rapid progression tochronic kidney failure and failure of other major organs. Hence the decision on which patients to treat should be based on the prognostic factors and the risk of progression. Also, IgA nephropathy recurs intransplants despite the use ofciclosporin,azathioprine ormycophenolate mofetil,cyclophosphamide,Isotretinoin andsteroids in these patients. There are persisting uncertainties, due to the limited number of patients included in the few controlled, randomized, studies performed to date. These studies hardly produce statistically-significant evidence regarding the heterogeneity of IgA nephropathy patients, the diversity of study treatment protocols, and the length of follow-up.[citation needed]
In cases wheretonsillitis is the precipitating factor for episodic hematuria, atonsillectomy has been claimed to reduce the frequency of those episodes. However, it does not reduce the incidence of progressivekidney failure.[10] Dietarygluten restriction, used to reduce mucosalantigen challenge, also has not been shown to preservekidney function.Phenytoin has also been tried without any benefit.[11]
A subset of IgA nephropathy patients, who haveminimal change disease on lightmicroscopy and clinically havenephrotic syndrome, show an exquisite response tosteroids, 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 6 months regimen of steroids in addition to other medications may lessen proteinuria and preserve renal function.[12] 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.[citation needed]
Cyclophosphamide (traded asendoxan andcytoxan) andIsotretinoin have commonly been used, often withanti-platelet/anticoagulants in patients with Aggressive Berger's disease, however, the side effect profile of these drugs, including long term risk ofmalignancy andsterility, made them an unfavorable choice for use in young adults. However, one recent study, in a carefully selected high risk population of patients with decliningGFR, showed that a combination of steroids andcyclophosphamide for the initial 3 months followed byazathioprine for a minimum of 2 years resulted in a significant preservation of renal function.[13] Other agents such asmycophenolate mofetil,ciclosporin andmizoribine have also been tried with varying results.
A 1994 study by Mayo Clinic found that long-term treatment withomega−3 fatty acid-rich fish oil, which does not have the drawbacks ofimmunosuppressive therapy, was associated with slight reduction of progression tokidney failure, without, however, reducingproteinuria in a subset of patients with high risk of worseningkidney function.[14] However, these results were not reproduced by other study groups and in two subsequent meta-analyses.[15][16]
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 ofblood pressure. The choice ofantihypertensive agent is open as long as the blood pressure is controlled to desired level. However,angiotensin converting enzyme inhibitors andangiotensin II receptor antagonists are favoured due to their anti-proteinuric effect.[citation needed]
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.[17]
Sparsentan is a therapy recently approved in the USA for treating primary IgA nephropathy.[18] It is a dualendothelinangiotensin 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.[19]
Male sex,proteinuria (especially > 2 g/day),hypertension,smoking,hyperlipidemia, older age, familial disease and elevatedcreatinine concentrations are markers of a poor outcome. Frankhematuria has shown discordant results with most studies showing a better prognosis, perhaps related to the early diagnosis, except for one group which reported a poorer prognosis. Proteinuria and hypertension are the most powerful prognostic factors in this group.[20]
Certain other features found by kidneybiopsy, such as interstitial scarring, are associated with a poor prognosis. ACE genepolymorphism has recently been shown to have an impact with the DDgenotype associated more commonly with progression tokidney failure.[citation needed]
Disease progression in IgAN can be predicted at the time ofkidney biopsy by a risk-prediction tool.[21]
Men are affected three times as often as women. There is also marked geographic variation in the prevalence of IgA nephropathy throughout the world. It is the most common glomerular disease in theFar East andSoutheast Asia, accounting for almost half of all patients with glomerular disease;[citation needed] however, it accounts for only about 25% of the proportion in Europeans and about 10% among North Americans, with African–Americans having a very low prevalence of about 2%.[citation needed] A confounding factor in this analysis is the existing policy ofscreening and use of kidney biopsy as an investigative tool. School children in Japan and army recruits in Singapore undergo routineurinalysis, and any suspicious abnormality is pursued with a kidney biopsy, which might partly explain the high observedincidence of IgA nephropathy in those countries.[citation needed]
Though various associations have been described, no consistent pattern pointing to a single susceptible gene has been identified to date. Associations described include those with C4 null allele, factor B Bf alleles, MHC antigens and IgA isotypes. ACEgenepolymorphism (D allele) is associated with progression of kidney failure, similar to its association with other causes ofchronic kidney failure. However, more than 90% of cases of IgA nephropathy are sporadic, with a few large pedigrees described fromKentucky and Italy (Online Mendelian Inheritance in Man (OMIM):161950).[citation needed]
William Heberden the elder first described the disease in 1801 in a 5-year-old child with abdominal pain,hematuria,hematochezia, and purpura of the legs.[22] In 1837,Johann Lukas Schönlein described a syndrome of purpura associated with joint pain and urinary precipitates in children.Eduard Heinrich Henoch, a student of Schönlein's, further associated abdominal pain and renal involvement with the syndrome.[citation needed]
In 1968, Jean Berger (1930–2011), a pioneering Frenchnephrologist, with co-author electron microscopist Nicole Hinglais, was the first to describe IgA deposition in this form ofglomerulonephritis and it is consequently sometimes called Berger's disease.[23]