- IgA nephropathy
Name = IgA nephropathy
ICD9 = ICD9|583.9
OMIM = 161950
MedlinePlus = 000466
eMedicineSubj = med
eMedicineTopic = 886
DiseasesDB = 1353
MeshID = D005922
IgA nephropathy (also known as "IgA nephritis", "IgAN", "Berger's disease" and "synpharyngitic glomerulonephritis") is a form of
glomerulonephritis( inflammationof the glomeruli of the kidney). This should not be confused with Buerger's disease, an unrelated condition.
IgA nephropathy is the most common glomerulonephritis throughout the world. Primary IgA nephropathy is characterized by deposition of the
IgA antibodyin the glomerulus. There are other diseases associated with glomerular IgA deposits, the most common being Henoch-Schönlein purpura, which is considered by many to be a systemic form of IgA nephropathy. Henoch-Schönlein purpura presents with a characteristic skin rash, occurs more commonly in young adults (16-35 yrs old) and is associated with a more benign prognosis than IgA nephropathy, which typically presents with hematuriain adults and may lead to chronic renal failure.
igns and symptoms
The classic presentation (in 40-50% of the cases) is episodic frank
hematuriawhich usually starts within a day of an upper respiratory tract infection(hence "synpharyngitic", as opposed to post-streptococcal glomerulonephritiswhich occurs some time after an initial infection). Flank pain can also occur. The frank hematuria resolves after a few days, though the microscopic hematuriapersists. These episodes occur on an irregular basis, and in most patients, this eventually stops (although it can take many years). Renal function usually remains normal, though rarely, acute renal failuremay occur (see below). This presentation is more common in younger adults.
A smaller proportion (20-30%), usually the older population, have microscopic hematuria and
proteinuria(less than 2 grams of protein per 24 hours). These patients may not have any symptoms and are only picked up if a doctor decides to take a urine sample. Hence, the disease is picked up more commonly in situations where screening of urine is compulsory, e.g. schoolchildren in Japan.
Very rarely (5% each), the presenting history is:
Nephrotic syndrome(excessive protein loss in the urine, associated with an excellent prognosis)
Acute renal failure(either as a complication of the frank hematuria, when it usually recovers, or due to rapidly progressive glomerulonephritiswhich often leads to chronic renal failure)
Chronic renal failure(no previous symptoms, presents with anemia, hypertensionand other symptoms of renal failure, in people who probably had longstanding undetected microscopic hematuria and/or proteinuria)
A variety of systemic diseases are associated with IgA nephropathy such as
liver failure, celiac disease, rheumatoid arthritis, Reiter's disease, ankylosing spondylitisand HIV. Diagnosis of IgA Nephropathy and a search for any associated disease occasionally reveals such an underlying serious systemic disease. Occasionally, there are simultaneous symptoms of Henoch-Schönlein purpura; see below for more details on the association.
For an adult patient with isolated
hematuria, tests such as ultrasound of the kidney and cystoscopyare usually done first to pinpoint the source of the bleeding. These tests would rule out kidney stonesand 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 directly. A urinalysiswill show red blood cells, usually as red cell urinary casts. Proteinuria, usually less than 2 grams per day, also may be present. Other renalcauses of isolated hematuria include thin basement membrane diseaseand Alport syndrome, the latter being a hereditary diseaseassociated with hearing impairment. A kidney biopsy is necessary to confirm the diagnosis. The biopsy specimen shows proliferation of the mesangium, with IgA deposits on immunofluorescenceand electron microscopy. However, all 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.
blood tests done to aid in the diagnosis include CRP or ESR, complement levels, ANA, ANCAand LDH. Protein electrophoresisand immunoglobulin levels can show increased IgA1 in 30% to 50% of all patients. may be normal or reduced. Tests such as electrolytes, renal function( creatinine, urea), total protein, serum albuminhelp in establishing the prognosis. Other tests such as bleeding time, full blood count, PT and PTT are done before performing a biopsy.
The disease derives its name from deposits of Immunoglobulin A (IgA) in a blotchy pattern in the mesangium (on
immunofluorescence), the heart of the renal glomerulus. As a rule, this affects the whole kidney. The tissue changes gradually from being hypercellular to depositing extracellular matrixproteins, and finally fibrosis.
There is no clear known explanation for the accumulation of the IgA. Exogenous
antigens 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.
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 O-glycosylated on a number of
serineand threonineresidues in a special proline-rich hinge region. Deficiency of these sugars appears to lead to polymerisation of the IgA molecule in tissues, especially the glomerular mesangium. A similar mechanism has been claimed to underly Henoch-Schönlein purpura(HSP), a vasculitisthat mainly affects children and can feature renal involvement that is almost indistinguishable from IgA nephritis.
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 systemrather 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.
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 hematuria, a group with a generally favourable prognosiswill be excluded. If, in contrast, all such patients are biopsied, then the group with isolated microscopic hematuriaand 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, has been shown to have a not-so-benign long term outcome. Though most reports describe IgA nephropathy 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 renal failure. In general, the entry into chronic renal failureis slow as compared to most other glomerulonephritis– occurring over a time scale of 30 years or more (in contrast to the 5 to 15 years in other glomerulonephritis). This may reflect the earlier diagnosis made due to frank hematuria.
Complete remission, i.e. a normal urinalysis, occurs rarely in adults, in about 5% of cases. Thus, even in those with normal
renal functionafter a decade or two, urinary abnormalities persist in the great majority. In contrast, 30 – 50% of children may have a normal urinalysis at the end of 10 years. However, given the very slow evolution of this disease, the longer term (20 – 30 years) outcome of such patients is not yet established.
Overall, though the renal survival is 80 – 90% after 10 years, at least 25% and may be up to 45% of adult patients will eventually develop end stage renal disease.
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 recurrent
hematuriaup to a rapid progression to chronic renal failure. Hence the decision on which patients to treat should be based on the prognostic factors and the risk of progression. Also, IgA nephropathy recurs in transplants despite the use of ciclosporin, azathioprineor mycophenolate mofetiland steroids in these patients. There are persisting uncertainties, due to the limited number of patients included in the few controlled randomized studies performed to date, which hardly produce statistically significant evidence regarding the heterogeneity of IgA nephropathy patients, the diversity of study treatment protocols, and the length of follow-up.
Patients with isolated hematuria,
proteinuria< 1 g/day and normal renal functionhave a benign course and are generally just followed up annually. In cases where tonsillitisis the precipitating factor for episodic hematuria, tonsillectomyhas been claimed to reduce the frequency of those episodes. However, it does not reduce the incidence of progressive renal failure. [cite journal |author=Xie Y, Chen X, Nishi S, Narita I, Gejyo F |title=Relationship between tonsils and IgA nephropathy as well as indications of tonsillectomy |journal=Kidney Int. |volume=65 |issue=4 |pages=1135–44 |year=2004 |pmid=15086452 |doi=10.1111/j.1523-1755.2004.00486.x |url=] Also, the natural history of the disease is such that episodes of frank hematuriareduce over time, independent of any specific treatment. Similarly, prophylactic antibiotics have not been proven to be beneficial. Dietary glutenrestriction, used to reduce mucosal antigenchallenge, also has not been shown to preserve renal function. Phenytoinhas been also been tried without any benefit [cite journal |author=Clarkson AR, Seymour AE, Woodroffe AJ, McKenzie PE, Chan YL, Wootton AM |title=Controlled trial of phenytoin therapy in IgA nephropathy |journal=Clin. Nephrol. |volume=13 |issue=5 |pages=215–8 |year=1980 |pmid=6994960 |doi= |url=]
A subset of IgA nephropathy patients, who have
minimal change diseaseon light microscopyand 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 preserved renal functionand proteinuria (1-3.5 g/day), a recent prospective study has shown that 6 months regimen of steroids may lessen proteinuria and preserve renal function. [cite journal |author=Kobayashi Y, Hiki Y, Kokubo T, Horii A, Tateno S |title=Steroid therapy during the early stage of progressive IgA nephropathy. A 10-year follow-up study |journal=Nephron |volume=72 |issue=2 |pages=237–42 |year=1996 |pmid=8684533 |doi= |url=] However, the risks of long-term steroid use have to be weighed in such cases. It should be noted that 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. Cyclophosphamidehad been used in combination with anti-platelet/ anticoagulants in unselected IgA nephropathy patients with conflicting results. Also, the side effect profile of this drug, including long term risk of malignancyand sterility, made it 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 cyclophosphamidefor the initial 3 months followed by azathioprinefor a minimum of 2 years resulted in a significant preservation of renal function. [cite journal |author=Ballardie FW, Roberts IS |title=Controlled prospective trial of prednisolone and cytotoxics in progressive IgA nephropathy |journal=J. Am. Soc. Nephrol. |volume=13 |issue=1 |pages=142–8 |year=2002 |pmid=11752031 |doi= |url=http://jasn.asnjournals.org/cgi/pmidlookup?view=long&pmid=11752031] Other agents such as mycophenolate mofetil, ciclosporinand mizoribinehave also been tried with varying results. A study from Mayo Clinic did show that long term treatment with omega-3 fatty acidsresults in reduction of progression to renal failure, without, however, reducing proteinuriain a subset of patients with high risk of worsening kidney function. [cite journal |author=Donadio JV, Bergstralh EJ, Offord KP, Spencer DC, Holley KE |title=A controlled trial of fish oil in IgA nephropathy. Mayo Nephrology Collaborative Group |journal=N. Engl. J. Med. |volume=331 |issue=18 |pages=1194–9 |year=1994 |pmid=7935657 |doi= |url=http://content.nejm.org/cgi/pmidlookup?view=short&pmid=7935657&promo=ONFLNS19 ] However, these results have not been reproduced by other study groups and in two subsequent meta-analyses. [cite journal |author=Strippoli GF, Manno C, Schena FP |title=An "evidence-based" survey of therapeutic options for IgA nephropathy: assessment and criticism |journal=Am. J. Kidney Dis. |volume=41 |issue=6 |pages=1129–39 |year=2003 |pmid=12776264 |doi= |url=http://linkinghub.elsevier.com/retrieve/pii/S0272638603003445] [cite journal |author=Dillon JJ |title=Fish oil therapy for IgA nephropathy: efficacy and interstudy variability |journal=J. Am. Soc. Nephrol. |volume=8 |issue=11 |pages=1739–44 |year=1997 |pmid=9355077 |doi= |url=http://jasn.asnjournals.org/cgi/pmidlookup?view=long&pmid=9355077] However, fish oil therapy does not have the drawbacks of immunosuppressive therapy. Also, apart from its unpleasant taste and abdominal discomfort, it is relatively safe to consume.
The events that tend to progressive renal failure are not unique to IgA nephropathy and non-specific measures to reduce the same would be equally useful. These include low-protein diet and optimal control of
blood pressure. The choice of the antihypertensiveagent is open as long as the blood pressure is controlled to desired level. However, Angiotensin converting enzyme inhibitors and Angiotensin II receptor antagonists are favoured due to their anti-proteinuric effect.
Though various associations have been described, no consistent pattern pointing to a single susceptible gene has been yet identified. Associations described include those with C4 null allele, factor B Bf alleles, MHC antigens and IgA isotypes. ACE
genepolymorphism (D allele) is associated with progression of renal failure, similar to its association with other causes of chronic renal failure. However, more than 90% of cases of IgA nephropathy are sporadic, with a few large pedigrees described from Kentuckyand Italy(OMIM|161950).
proteinuria(especially > 2 g/day), hypertension, smoking, hyperlipidemia, older age, familial disease and elevated creatinineconcentrations are markers of a poor outcome. Frank hematuriahas 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. Proteinuriaand hypertensionare the most powerful prognostic factors in this group. [cite journal |author=Bartosik LP, Lajoie G, Sugar L, Cattran DC |title=Predicting progression in IgA nephropathy |journal=Am. J. Kidney Dis. |volume=38 |issue=4 |pages=728–35 |year=2001 |pmid=11576875 |doi= |url=http://linkinghub.elsevier.com/retrieve/pii/S0272638601420440]
There are certain other features on kidney biopsy such as interstitial scarring which are associated with a poor prognosis. ACE gene polymorphism has been recently shown to have an impact with the DD
genotypeassociated more commonly with progression to renal failure.
Men are affected three times as often as women. There is also a striking geographic variation in the prevalence of IgA nephropathy throughout the world. It is the most common glomerular disease in the
Far Eastand Southeast Asia, comprising almost half of all the patients with glomerular disease. However, it comprises only about 25% of the proportion in European and about 10% among North Americans, with African–Americans having a very low prevalence of about 2%. A confounding factor in this analysis is the existing policy of screening and use of kidney biopsy as an investigative tool. School children in Japanundergo routine urinalysis(as do Army recruits in Singapore) and any suspicious abnormality is pursued with a kidney biopsy, which might partly explain the high incidence of IgA nephropathy in those countries.
Heberden first described the disease in 1801 in a 5-year-old child with abdominal pain,
hematuria, hematochezia, and purpura of the legs. In 1837, Johann Schönlein described a syndrome of purpura associated with joint pain and urinary precipitates in children. Eduard Henoch, a student of Schönlein's, further associated abdominal pain and renal involvement with the syndrome. Jean Berger and Hinglais, in 1968, were the first to describe IgA deposition in this form of glomerulonephritis(hence, Berger’s disease). [cite journal |author=Berger J, Hinglais N |title=Les depots intercapillaires d'IgA-IgG |journal=J Urol Nephrol |volume=74 |issue= |pages=694-5 |year=1968 |pmid= |doi= |url= ]
* [http://www.igan.ca/ The Foundation for IgA Nephropathy]
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