Medicine:IgA nephropathy

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Short description: Disease of the kidney
"Berger's disease" redirects here. It is not to be confused with Buerger's disease or IgA vasculitis.
IgA nephropathy
Other namesIgA nephritis, Berger's disease
Immunoglobulin A dimer
SpecialtyNephrology
Rheumatology

IgA nephropathy (IgAN), also known as Berger's disease (/bɛərˈʒeɪ/) (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.[1]

IgA nephropathy is the most common glomerulonephritis worldwide; the global incidence is 2.5/100,000 per year amongst adults.[2] Aggressive Berger's disease is on the NORD list of rare diseases.[3] 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.[4] 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

  • 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)


Morphology

Pathophysiology

Immunostaining showing IgA in the glomerulus of a patient with Henoch-Schönlein nephritis.
File:IgA Nephropathy.webm
The pathophysiology, signs and symptoms, and treatment of IgA nephropathy.

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.[5]


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.[6][7]

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.[8] 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.[9]

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.[10][11]

Natural history



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.[12] 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.[13] 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

Treatment

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.[14] Dietary gluten restriction, used to reduce mucosal antigen challenge, also has not been shown to preserve kidney function. Phenytoin has also been tried without any benefit.[15]

A subset of IgA nephropathy patients, who have minimal change disease on light microscopy and clinically have nephrotic syndrome, show an exquisite response to steroids, 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.[16] 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/anticoagulants in patients with Aggressive Berger's disease, however, the side effect profile of these drugs, including long term risk of malignancy and sterility, 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.[17] 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.[18] However, these results were not reproduced by other study groups and in two subsequent meta-analyses.[19][20]


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.[21]

Sparsentan is a therapy recently approved in the USA for treating primary IgA nephropathy.[22] 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.[23]

Sibeprenlimab (Voyxact) was approved for medical use in the United States in November 2025.[24]

Prognosis

Male sex, proteinuria (especially > 2 g/day), hypertension, smoking, hyperlipidemia, older age, familial disease and elevated creatinine concentrations are markers of a poor outcome. Frank hematuria 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.[25]


Disease progression in IgAN can be predicted at the time of kidney biopsy by a risk-prediction tool.[26]

Epidemiology

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 the Far East and Southeast Asia, accounting for almost half of all patients with glomerular disease; 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|date=July 2016} lysis is the existing policy of screening and use of kidney biopsy as an investigative tool. School children in Japan and army recruits in Singapore undergo routine urinalysis, and any suspicious abnormality is pursued with a kidney biopsy, which might partly explain the high observed incidence of IgA nephropathy in those countries.[citation needed]

Genetics

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. ACE gene polymorphism (D allele) is associated with progression of kidney failure, similar to its association with other causes of chronic kidney failure. However, more than 90% of cases of IgA nephropathy are sporadic, with a few large pedigrees described from Kentucky and Italy (Online Mendelian Inheritance in Man (OMIM) 161950).

History

Dr Jean Berger

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.[27]

References

  1. ↑ Lai, Kar Neng, ed (2009) (in en). Recent Advances in Iga Nephropathy. World Scientific Publishing Co. Pte. Ltd.. doi:10.1142/9789812835871. ISBN 978-981-283-587-1. http://ebooks.worldscinet.com/ISBN/9789812835871/9789812835871.html. 
  2. ↑ Kiryluk, Krzysztof; Li, Yifu; Sanna-Cherchi, Simone; Rohanizadegan, Mersedeh; Suzuki, Hitoshi et al. (21 June 2012). "Geographic Differences in Genetic Susceptibility to IgA Nephropathy: GWAS Replication Study and Geospatial Risk Analysis". PLOS Genetics 8 (6). doi:10.1371/journal.pgen.1002765. PMID 22737082. 
  3. ↑ D'Amico, G (1987). "The commonest glomerulonephritis in the world: IgA nephropathy". Q J Med 64 (245): 709–27. PMID 3329736. 
  4. ↑ C, Davin J (2001). "What is the difference between IgA nephropathy and Henoch-Schönlein purpura nephritis?". Kidney International 59 (3): 823–34. doi:10.1046/j.1523-1755.2001.059003823.x. PMID 11231337. 
  5. ↑ Magistroni, Riccardo (2015). "New developments in the genetics, pathogenesis, and therapy of IgA nephropathy". Kidney International 88 (5): 974–89. doi:10.1038/ki.2015.252. PMID 26376134. 
  6. ↑ "Glycans in the immune system and The Altered Glycan Theory of Autoimmunity". J Autoimmun 57 (6): 1–13. 2015. doi:10.1016/j.jaut.2014.12.002. PMID 25578468. 
  7. ↑ "IgA nephropathy video in WikiMedia.". https://upload.wikimedia.org/wikipedia/commons/transcoded/3/31/IgA_Nephropathy.webm/IgA_Nephropathy.webm.720p.vp9.webm. 
  8. ↑ "O-glycosylation of serum IgA1 antibodies against mucosal and systemic antigens in IgA nephropathy.". J Am Soc Nephrol 17 (12): 3520–28. 2006. doi:10.1681/ASN.2006060658. PMID 17093066. 
  9. ↑ Suzuki, Hitoshi; Kiryluk, Krzysztof; Novak, Jan; Moldoveanu, Zina; Herr, Andrew; Renfrow, Matthew; Wyatt, Robert; Scolari, Francesco et al. (October 1, 2011). "The Pathophysiology of IgA Nephropathy". Journal of the American Society of Nephrology 22 (10): 1795–1803. doi:10.1681/ASN.2011050464. PMID 21949093. PMC 3892742. http://jasn.asnjournals.org/content/22/10/1795.short. 
  10. ↑ "IgA Nephropathy". https://www.lecturio.com/concepts/iga-nephropathy/. 
  11. ↑ "IgA Nephropathy". 24 December 2015. https://www.kidney.org/atoz/content/iganeph. 
  12. ↑ Liu, Lili; Khan, Atlas; Sanchez-Rodriguez, Elena; Zanoni, Francesca; Li, Yifu; Steers, Nicholas; Balderes, Olivia; Zhang, Junying et al. (2022-11-11). "Genetic regulation of serum IgA levels and susceptibility to common immune, infectious, kidney, and cardio-metabolic traits" (in en). Nature Communications 13 (1). doi:10.1038/s41467-022-34456-6. ISSN 2041-1723. PMID 36369178. PMC 9651905. https://www.nature.com/articles/s41467-022-34456-6. 
  13. ↑ Lin, Xu; Chen, Gui-Bing; Li, Ke-Yi; Xu, Ya-Juan (January 2025). "Causal relationship between IgA nephropathy and common neuropsychiatric disorders: A two-sample Mendelian randomization analysis" (in en). Journal of Affective Disorders 369: 782–788. doi:10.1016/j.jad.2024.10.012. https://linkinghub.elsevier.com/retrieve/pii/S0165032724016732. 
  14. ↑ "Relationship between tonsils and IgA nephropathy as well as indications of tonsillectomy". Kidney Int. 65 (4): 1135–44. 2004. doi:10.1111/j.1523-1755.2004.00486.x. PMID 15086452. 
  15. ↑ "Controlled trial of phenytoin therapy in IgA nephropathy". Clin. Nephrol. 13 (5): 215–18. 1980. PMID 6994960. 
  16. ↑ "Steroid therapy during the early stage of progressive IgA nephropathy. A 10-year follow-up study". Nephron 72 (2): 237–42. 1996. doi:10.1159/000188848. PMID 8684533. 
  17. ↑ "Controlled prospective trial of prednisolone and cytotoxics in progressive IgA nephropathy". J. Am. Soc. Nephrol. 13 (1): 142–48. 2002. doi:10.1681/ASN.V131142. PMID 11752031. http://jasn.asnjournals.org/cgi/pmidlookup?view=long&pmid=11752031. 
  18. ↑ "A controlled trial of fish oil in IgA nephropathy. Mayo Nephrology Collaborative Group". N. Engl. J. Med. 331 (18): 1194–99. 1994. doi:10.1056/NEJM199411033311804. PMID 7935657. 
  19. ↑ "An 'evidence-based' survey of therapeutic options for IgA nephropathy: assessment and criticism". Am. J. Kidney Dis. 41 (6): 1129–39. 2003. doi:10.1016/S0272-6386(03)00344-5. PMID 12776264. 
  20. ↑ Dillon JJ (1997). "Fish oil therapy for IgA nephropathy: efficacy and interstudy variability". J. Am. Soc. Nephrol. 8 (11): 1739–44. doi:10.1681/ASN.V8111739. PMID 9355077. http://jasn.asnjournals.org/cgi/pmidlookup?view=long&pmid=9355077. 
  21. ↑ "FDA approves first drug to decrease urine protein in IgA nephropathy, a rare kidney disease". 17 December 2021. https://www.fda.gov/drugs/fda-approves-first-drug-decrease-urine-protein-iga-nephropathy-rare-kidney-disease.  Public Domain This article incorporates text from this source, which is in the public domain.
  22. ↑ Syed, Y Y (April 2023). "Sparsentan: First Approval". Drugs 83 (6): 563–568. doi:10.1007/s40265-023-01864-x. PMID 37022667. 
  23. ↑ Rovin, Bard H; Barratt, Jonathan; Heerspink, Hiddo J L; Alpers, Charles E et al. (December 2, 2024). "Efficacy and safety of sparsentan versus irbesartan in patients with IgA nephropathy (PROTECT): 2-year results from a randomised, active-controlled, phase 3 trial". Thelancet 402 (10417): 2077–2090. doi:10.1016/S0140-6736(23)02302-4. PMID 37931634. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(23)02302-4/abstract. 
  24. ↑ "Otsuka Receives FDA Accelerated Approval for Voyxact (sibeprenlimab-szsi) for the Reduction of Proteinuria in Adults with Primary Immunoglobulin A Nephropathy (IgAN) at Risk for Disease Progression" (Press release). Otsuka Pharmaceutical. 26 November 2025. Retrieved 26 November 2025.
  25. ↑ "Predicting progression in IgA nephropathy". Am. J. Kidney Dis. 38 (4): 728–35. 2001. doi:10.1053/ajkd.2001.27689. PMID 11576875. 
  26. ↑ Barbour, Sean J.; Coppo, Rosanna; Zhang, Hong; Liu, Zhi-Hong; Suzuki, Yusuke; Matsuzaki, Keiichi; Katafuchi, Ritsuko; Er, Lee et al. (2019-07-01). "Evaluating a New International Risk-Prediction Tool in IgA Nephropathy". JAMA Internal Medicine 179 (7): 942–952. doi:10.1001/jamainternmed.2019.0600. ISSN 2168-6106. PMID 30980653. 
  27. ↑ "Les depots intercapillaires d'IgA-IgG". J Urol Nephrol 74: 694–95. 1968. 
  • IGA Nephropathy on National Institute of Diabetes and Digestive and Kidney Diseases
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