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| '''For patient information click [[{{PAGENAME}} (patient information)|here]]''' | | '''For patient information click [[{{PAGENAME}} (patient information)|here]]''' |
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| {{SI}} | | {{IgA nephropathy}} |
| {{CMG}}; '''Associate Editor-In-Chief:''' {{CZ}} | | {{CMG}};{{AE}} {{Rim}}; {{SH}}; {{OO}};{{APM}} |
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| ==Overview==
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| '''IgA nephropathy''' (also known as ''IgA nephritis'', ''IgAN'', '''''Berger's disease''''' and ''synpharyngitic glomerulonephritis'') is a form of [[glomerulonephritis]] ([[inflammation]] of the [[glomerulus|glomeruli]] of the [[kidney]]). This should not be confused with [[Buerger's disease]], an unrelated condition.
| | {{SK}} IgA nephritis; IgAN; Berger's disease; synpharyngitic glomerulonephritis, |
| | IgA glomerulonephritis, IgAN - IgA nephropathy, Immunoglobulin A nephropathy |
| | == [[IgA nephropathy overview|Overview]] == |
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| IgA nephropathy is the most common glomerulonephritis throughout the world. 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 [[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 [[hematuria]] in adults and may lead to [[chronic renal failure]].
| | == [[IgA nephropathy historical perspective|Historical Perspective]] == |
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| ==Epidemiology== | | == [[IgA nephropathy classification|Classification]] == |
| 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 East and 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 [[needle aspiration biopsy|biopsy]] as an investigative tool. School children in Japan undergo 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.
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| ==History== | | == [[IgA nephropathy pathophysiology|Pathophysiology]] == |
| 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): Berger J, Hinglais N. ''Les depots intercapillaires d'IgA-IgG''. J Urol Nephrol 1968;74:694-5.
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| ==Pathophysiology== | | == [[IgA nephropathy causes|Causes]] == |
| The disease derives its name from deposits of [[antibody|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 matrix]] proteins, and finally [[fibrosis]].
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| There is no clear known explanation for the accumulation of the IgA. Exogenous [[antigen]]s 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.
| | == [[IgA nephropathy differential diagnosis|Differentiating IgA nephropathy from other Diseases]] == |
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| 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|O-glycosylated]] on a number of [[serine]] and [[threonine]] residues in a special [[proline]]-rich hinge region. Deficiency of these sugars appears to lead to [[polymer]]isation of the IgA molecule in tissues, especially the glomerular mesangium. A similar mechanism has been claimed to underly [[Henoch-Schönlein purpura]] (HSP), a [[vasculitis]] that mainly affects children and can feature renal involvement that is almost indistinguishable from IgA nephritis.
| | == [[IgA nephropathy epidemiology and demographics|Epidemiology and Demographics]] == |
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| 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.
| | == [[IgA nephropathy risk factors|Risk Factors]] == |
| | ==[[IgA nephropathy screening|Screening]]== |
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| == Natural history == | | == [[IgA nephropathy natural history, complications and prognosis|Natural History, Complications and 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 (medicine)|screening]] policy. Similarly, the local policy for performing kidney [[needle aspiration biopsy|biopsy]] assumes a critical role; if it is a policy to simply observe patients with isolated [[hematuria]], 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.
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| 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 failure]] is 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 ğğglomerulonephritisüü). This may reflect the earlier diagnosis made due to frank hematuria.
| | == Diagnosis == |
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| Complete remission, i.e. a normal urinalysis, occurs rarely in adults, in about 5% of cases. Thus, even in those with normal [[renal function]] after 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.
| | [[IgA nephropathy diagnostic study of choice|Diagnostic Study of Choice]] | [[IgA nephropathy history and symptoms|History and Symptoms]] | [[IgA nephropathy physical examination|Physical Examination]] | [[IgA nephropathy laboratory findings|Laboratory Findings]] | [[IgA nephropathy electrocardiogram|Electrocardiogram]] | [[IgA nephropathy x ray|X-ray]] | [[IgA nephropathy CT|CT]] | [[IgA nephropathy MRI|MRI]] | [[IgA nephropathy echocardiography or ultrasound|Echocardiography or Ultrasound]] |[[IgA nephropathy other imaging findings|Other Imaging Findings]] | [[IgA nephropathy other diagnostic studies|Other Diagnostic Studies]] |
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| 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.
| | == Treatment == |
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| ==Genetics==
| | [[IgA nephropathy medical therapy|Medical Therapy]] | [[IgA nephropathy surgery|Surgery]] | [[IgA nephropathy primary prevention|Primary Prevention]] | [[IgA nephropathy secondary prevention|Secondary Prevention]] | [[IgA nephropathy cost-effectiveness of therapy|Cost-Effectiveness of Therapy]] | [[IgA nephropathy future or investigational therapies|Future or Investigational Therapies]] |
| 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 [[gene]] [[Polymorphism (biology)|polymorphism]] (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 Kentucky and Italy ({{OMIM|161950}}).
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| ==Signs and symptoms==
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| The classic presentation (in 40-50% of the cases) is episodic frank [[hematuria]] which usually starts within a day of an [[upper respiratory tract infection]] (hence ''synpharyngitic'', as opposed to [[post-streptococcal glomerulonephritis]] which occurs some time after an initial infection). Flank pain can also occur. The frank hematuria resolves after a few days, though the [[microscopic hematuria]] persists. 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 failure]] may occur (see below). This presentation is more common in younger adults.
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| 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. school children in Japan.
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| Very rarely (5% each), the presenting history is:
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| * [[Nephrotic syndrome]] (excessive protein loss in the urine, associated with an excellent prognosis)
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| * [[Acute renal failure]] (either as a complication of the frank hematuria, when it usually recovers, or due to [[rapidly progressive glomerulonephritis]] which often leads to [[chronic renal failure]])
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| * [[Chronic renal failure]] (no previous symptoms, presents with [[anemia]], [[hypertension]] and other symptoms of renal failure, in people who probably had longstanding undetected microscopic hematuria and/or proteinuria)
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| A variety of systemic diseases are associated with IgA nephropathy such as [[liver failure]], [[coeliac disease]], [[rheumatoid arthritis]], [[Reiter's disease]], [[ankylosing spondylitis]] and [[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.
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| ==Diagnosis==
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| For an adult patient with isolated [[hematuria]], tests such as [[Medical ultrasonography|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 [[urology|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 [[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]]. A kidney [[needle aspiration biopsy|biopsy]] is necessary to confirm the diagnosis. The biopsy specimen shows proliferation of the [[mesangium]], with IgA deposits on [[immunofluorescence]] and [[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]].
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| Other [[blood test]]s done to aid in the diagnosis include [[C-reactive protein|CRP]] or [[erythrocyte sedimentation rate|ESR]], [[Complement system|complement]] levels, [[Anti-nuclear antibody|ANA]], ANCA and [[lactate dehydrogenase|LDH]]. [[Protein electrophoresis]] and [[antibody|immunoglobulin]] levels can show increased IgA1 in 30% to 50% of all patients. may be normal or reduced. Tests such as [[electrolyte]]s, [[renal function]] ([[creatinine]], [[urea]]), total protein, [[serum albumin]] help in establishing the [[prognosis]]. Other tests such as [[bleeding time]], [[full blood count]], [[Prothrombin time|PT]] and [[Partial thromboplastin time|PTT]] are done before performing a biopsy.
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| ==Therapy==
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| 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 [[hematuria]] up 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 [[transplant]]s despite the use of [[ciclosporin]], [[azathioprine]] or [[mycophenolate mofetil]] and [[steroid]]s 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.
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| Patients with isolated hematuria, [[proteinuria]] < 1 g/day and normal [[renal function]] have a benign course and are generally just followed up annually. In cases where [[tonsillitis]] is the precipitating factor for episodic hematuria, [[tonsillectomy]] has been claimed to reduce the frequency of those episodes. However, it does not reduce the incidence of progressive [[chronic renal failure|renal failure]]{{ref|Xie}}. Also, the natural history of the disease is such that episodes of frank [[hematuria]] reduce over time, independent of any specific treatment. Similarly, [[prophylactic]] [[antibiotic]]s have not been proven to be beneficial. Dietary [[gluten]] restriction, used to reduce mucosal [[antigen]] challenge, also has not been shown to preserve [[renal function]]. [[Phenytoin]] has been also been tried without any benefit{{ref|Clarkson}}.
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| A subset of IgA nephropathy patients, who have [[minimal change disease]] on light [[microscopy]] and clinically have [[nephrotic syndrome]], show an exquisite response to [[steroid]]s, 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 function]] and 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{{ref|Kobayashi}}. 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.
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| [[Cyclophosphamide]] had been used in combination with antiplatelets / [[anticoagulant]]s in unselected IgA nephropathy patients with conflicting results. Also, the side effect profile of this drug, including long term risk of [[malignancy]] and [[infertility|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 [[cyclophosphamide]] for the initial 3 months followed by [[azathioprine]] for a minimum of 2 years resulted in a significant preservation of renal function {{ref|Ballardie}}. Other agents such as [[mycophenolate mofetil]], [[ciclosporin]] and mizoribine have also been tried with varying results.
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| A study from Mayo Clinic did show that long term treatment with omega-3 fatty acids results in reduction of progression to [[renal failure]], without, however, reducing [[proteinuria]] in a subset of patients with high risk of worsening [[kidney function]]{{ref|Donadio}}. However, these results have not been reproduced by other study groups and in two subsequent meta-analyses {{ref|Strippoli}}{{ref|Dillon}}. 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.
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| 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 [[antihypertensive]] agent is open as long as the blood pressure is controlled to desired level. However, [[Angiotensin converting enzyme inhibitor]]s and [[Angiotensin II receptor antagonist]]s are favoured due to their anti-proteinuric effect.
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| ==Prognosis==
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| Male gender, [[proteinuria]] (especially > 2 g/day), [[hypertension]], [[Tobacco smoking|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{{ref|Bartosik}}.
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| There are certain other features on kidney [[needle aspiration biopsy|biopsy]] such as interstitial scarring which are associated with a poor prognosis. ACE gene [[Polymorphism (biology)|polymorphism]] has been recently shown to have an impact with the DD [[genotype]] associated more commonly with progression to [[renal failure]].
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| ==References==
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| {{reflist|2}}
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| #{{note|Xie}}Xie Y, Chen X, Nishi S, Narita I, Gejyo F. Relationship between tonsils and IgA nephropathy as well as indications of tonsillectomy. ''Kidney Int''. 2004;65(4):1135-44. PMID 15086452
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| #{{note|Clarkson}}Clarkson AR, Seymour AE, Woodroffe AJ, et al. Controlled trial of phenytoin therapy in IgA nephropathy. ''Clin Nephrol''. 1980;13(5):215-8. PMID 6994960
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| #{{note|Kobayashi}}Kobayashi Y, Hiki Y, Kokubo T, et al: Steroid therapy during the early stage of progressive IgA nephropathy: A 10-year follow-up study. ''Nephron''. 1996;72:237-242 PMID 8684533.
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| #{{note|Ballardie}}Ballardie FW, Roberts IS: Controlled prospective trial of prednisolone and cytotoxics in progressive IgA nephropathy. ''J Am Soc Nephrol''. 2002;13:142-148 PMID 11752031.
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| #{{note|Donadio}}Donadio JV Jr, Bergstralh EJ, Offord KP, Spencer DC, Holley KE: A controlled trial of fish oil in IgA nephropathy. Mayo Nephrology Collaborative Group.''N Engl J Med''. 1994;331(18):1194-9 PMID 7935657
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| #{{note|Strippoli}}Strippoli G, Mano C, Schena F. An ‘evidence-based’ survey of therapeutic options for IgA nephropathy: assessment and criticism. ''Am J Kidney Dis''. 2003;41:1129–1139 PMID 12776264
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| #{{note|Dillon}}Dillon JJ. Fish oil therapy for IgA nephropathy: efficacy and interstudy variability. ''J Am Soc Nephrol''. 1997;8:1739–1744 PMID 9355077
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| #{{note|Bartosik}}Bartosik LP, Lajoie G, Sugar L, Cattran DC. Predicting progression in IgA nephropathy. ''Am J Kidney Dis''. 2001;38(4):728-35. PMID 11576875
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| | ==Case Studies== |
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| | [[IgA nephropathy case study one|Case #1]] |
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