IgA nephropathy
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor-In-Chief: Cafer Zorkun, M.D., Ph.D. [2]
Synonyms and keywords: IgA nephritis; IgAN; Berger's disease; synpharyngitic glomerulonephritis
Genetics
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 (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 (Online Mendelian Inheritance in Man (OMIM) 161950).
Signs and symptoms
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.
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.
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 glomerulonephritis which often leads to chronic renal failure)
- 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)
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.
Diagnosis
For an adult patient with isolated hematuria, tests such as 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 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 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.
Other blood tests done to aid in the diagnosis include CRP or ESR, complement levels, ANA, ANCA and LDH. Protein electrophoresis and 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 albumin help in establishing the prognosis. Other tests such as bleeding time, full blood count, PT and PTT are done before performing a biopsy.
Therapy
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 transplants despite the use of ciclosporin, azathioprine or mycophenolate mofetil and 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 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 renal failure[3]. Also, the natural history of the disease is such that episodes of frank hematuria reduce over time, independent of any specific treatment. Similarly, prophylactic antibiotics 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[4].
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 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[5]. 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.
Cyclophosphamide had been used in combination with antiplatelets / anticoagulants in unselected IgA nephropathy patients with conflicting results. Also, the side effect profile of this drug, including long term risk of malignancy and 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 [6]. Other agents such as mycophenolate mofetil, ciclosporin and mizoribine have also been tried with varying results.
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[7]. However, these results have not been reproduced by other study groups and in two subsequent meta-analyses [8][9]. 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 antihypertensive agent 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.
Prognosis
Male gender, 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[10]. 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 genotype associated more commonly with progression to renal failure.
References
- ^ 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
- ^ 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
- ^ 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.
- ^ 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.
- ^ 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
- ^ 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
- ^ Dillon JJ. Fish oil therapy for IgA nephropathy: efficacy and interstudy variability. J Am Soc Nephrol. 1997;8:1739–1744 PMID 9355077
- ^ Bartosik LP, Lajoie G, Sugar L, Cattran DC. Predicting progression in IgA nephropathy. Am J Kidney Dis. 2001;38(4):728-35. PMID 11576875