IgA nephropathy overview
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Ali Poyan Mehr, M.D. [2] Associate Editor(s)-in-Chief: Dildar Hussain, MBBS [3] Olufunmilola Olubukola M.D.[4] Ayesha A. Khan, MD[5]
Overview
IgA nephropathy (Berger’s disease) is considered the most common primary chronic glomerulonephritis. IgA nephropathy is defined immune-histologically by mesangial deposits of IgA, often accompanied by less intense staining for IgM and/or IgG and C3, in the absence of a systemic disease. IgA nephropathy has been differentiated from Henoch- Schönlein purpura (HSP), which is clearly a systemic illness with vasculitis. The clinical syndrome of IgA nephropathy is often unpredictable, although classically it is recognized as a nephritic syndrome with a presentation of recurrent painless gross hematuria following a respiratory or gastrointestinal tract infection in a young male patient. Nonetheless, asymptomatic IgA nephropathy with microscopic hematuria is not uncommon. Although not frequently performed, the definitive diagnosis to confirm the clinical suspicion of IgA nephropathy is kidney biopsy that not only carries diagnostic benefit, but also has prognostic implications. IgA nephropathy is a progressive kidney disease that often leads to End Stage Renal Disease (ESRD) due to lack of specific treatments or therapies for this disease. IgA Nephropathy is diagnosed by electron microscopy of a kidney biopsy specimen showing immunological deposits of predominantly glycosylated but non-galactosed linked IgA1 in the mesangium of the kidney glomeruli. These IgA immune complexes deposit comprises of mainly glycosylated immunoglobulin A1 (IgA) with some complement C3 and immunoglobulins G/M (IgG/ IgM).
Historical Perspective
IgA nephropathy (Berger disease) was first described by Jean Berger, a pathologist, and Nicole Hinglais, an electron microscopist, in 1968 in France.
Classification
IgA nephropathy may be classified according to its association to other pathology or by its histological features. When IgA nephropathy occurs in isolation, it is called "primary IgA nephropathy". In converse, if IgA nephropathy is a consequence of a more systemic disease, it is called "secondary IgA nephropathy". Additionally, IgA nephropathy may be histologically classified according to the oxford classification of IgA nephropathy as mesangial hypercellularity, segmental glomerulosclerosis, endocapillary hypercellularity, or tubular atrophy/interstitial fibrosis.
Pathophysiology
IgA nephropathy is characterized by the presence of aberrant IgA1 immunoglobulins deposited on the glomerular mesangium. IgG and IgM may also be present to a much lower extent. On the other hand, serum IgA1 levels are elevated in patients with IgA nephropathy in 30-50% of cases. IgA1 subtypes contain galactose-deficient 3-6 O-glycans that may act as binding sites for anti-N-acetyl-galactosamine antibodies. These antibodies have been shown to be expressed following antigenic exposure to certain infectious agents. Currently, IgA nephropathy is believed to be a 4-hit process that eventually leads to IgA deposition on glomerular mesangium. Although mesangial deposition is most commonly seen in patients with IgA nephropathy, other pathological features might still be present.
Causes
The cause of primary IgA nephropathy is unknown. Additionally, there are no known infectious or environmental associated factors. However, IgA nephropathy is associated with some genetic mutations and familial clustering as a postulated cause of primary IgAN. Liver cirrhosis, celiac disease, HIV infection are the most common etiologies associated with glomerular IgA deposits and thus secondary IgA nephropathy.
Epidemiology and Demographics
IgA nephropathy is currently the most common cause of primary glomerulonephritis globally, and it is the most common primary chronic glomerulonephritis in the developed world. IgA nephropathy comprises approximately 10% of all biopsy-proven glomerulonephritis in the USA, 20% of those in Europe and 40-50% of those in Asia. The kidney biopsies are not routinely performed for all patients with kidney diseases; hence, IgA nephropathy is perhaps under-diagnosed, and its true prevalence remains unknown.
Risk Factors
Several risk factors have been found to be associated with IgA nephropathy, most of which seem to be associated with disease outcome and progression into ESRD rather than disease development. Male gender, native Americans and American and European populations around the pacific rim and asian populations such as China and Japan are more commonly diagnosed with IgA nephropathy.
Screening
According to the National Kidney Foundation guidelines for glomerulonephritis, screening is currently not recommended for IgA nephropathy.
Natural History, Complications, and Prognosis
The clinical course of IgA nephropathy varies widely between patients. Although it is generally regarded as a benign disease, emerging data has shown that progression to ESRD and death are more common than originally believed. Some patients rapidly progress into ESRD; but the majority experience a stable kidney function following diagnosis. Commonly, the progression of IgA nephropathy is slower than other notorious glomerular disease. Approximately 20-30% of patients with IgA nephropathy progress to ESRD after 10 years and up to 30-50% of patients develop ESRD over 20 years.
Diagnosis
Diagnostic Study of Choice
History and Symptoms
The majority of patients with IgA nephropathy are asymptomatic. Some patients with IgA nephropathy may develop intermittent gross hematuria which is often termed as synpharyngitic hematuria, because it occurs after the episodes of bacterial tonsillitis or viral URTI's. The patient may also have a positive history of flank pain, low grade fever.
Physical Examination
Patients with IgA nephropathy usually appear normal and usually have no significant clinical finding upon physical examination. However, some of the patients may present with low-grade fever, high blood pressure with normal pulse pressure, and pitting edema of the lower extremities in the late stage if the patient develops ESRD.
Laboratory Findings
There are no specific and sensitive diagnostic laboratory findings associated with IgA nephropathy. However all patients with biopsy-proven IgA nephropathy are assessed for secondary causes to rule out common causes of secondary IgA nephropathy. The viral serologies for HIV, HBV, HCV, liver function tests, and electrophoresis of serum immunoglobulins are performed. Blood pressure measurement, serum creatinine to estimate glomerular filtration rate , proteinuria, and pathological features are monitored to assess the risk of progression of the disease.
Electrocardiogram
There are no ECG findings associated with IgA nephropathy.
X-ray
There are no x-ray findings associated with IgA nephropathy.
Echocardiography and Ultrasound
For an adult patient with isolated hematuria, ultrasound of the kidney is usually done first to pinpoint the source of the bleeding. The ultrasonography would rule out kidney stones and bladder cancer, which are the two other common urological causes of hematuria.
CT scan
There are no CT scan findings associated with IgA nephropathy.
MRI
There are no MRI findings associated with IgA nephropathy.
Other Imaging Findings
There are no other imaging findings associated with IgA nephropathy.
Other Diagnostic Studies
For an adult patient with isolated hematuria, diagnostic studies such as ultrasound of the kidney and cystoscopy are usually done first to pinpoint the source of the bleeding. These diagnostic studies would rule out kidney stones and bladder cancer, two other common urological causes of hematuria.
Treatment
Medical Therapy
Surgery
The mainstay of treatment for IgA nephropathy is medical therapy. Tonsillectomy is usually reserved for patients with recurrent infections and renal transplant in patients with ESRD due to IgA nephropathy and renal transplantation in patients with ESRD due to IgA nephropathy.
Primary Prevention
There are no established measures for the primary prevention of IgA nephropathy.
Secondary Prevention
There are no established measures for the secondary prevention of IgA nephropathy.