IgA nephropathy

IgA nephropathy
Other names: IgA nephritis, Berger's disease, synpharyngitic glomerulonephritis
Immunoglobulin A dimer
Pronunciation	Berger's disease (/bɛərˈʒeɪ/
Specialty	Nephrology
Symptoms	None, blood in the urine, foamy urine, swelling of the legs[1]
Complications	High blood pressure, kidney failure, heart disease, Henoch-Schönlein purpura[1]
Usual onset	Late childhood to late 30s[1]
Duration	Long term[2]
Causes	Autoimmune disease[2]
Risk factors	Family history, HIV/AIDS, and hepatitis[1][2]
Diagnostic method	Suspected based on blood and urine tests, confirmed by a kidney biopsy[1]
Differential diagnosis	Lupus nephritis, nephrotic syndrome, membranoproliferative glomerulonephritis, Henoch-Schönlein purpura[2]
Prevention	None[2]
Treatment	Immunosuppressants, blood pressure medication, kidney transplant[2]
Prognosis	Often good[2]
Frequency	Relatively common[1]

IgA nephropathy (IgAN), also known as Berger's disease, is a disease of the kidney that occurs when IgA build up and results in inflammation.^[1] Early on there are typically no symptoms.^[1] As the disease worsens bloody and foamy urine may occur.^[1] Other symptoms may include swelling of the legs.^[1] Complications may include high blood pressure, kidney failure, heart disease, and Henoch-Schönlein purpura.^[1]

Risk factors include family history, HIV/AIDS, and hepatitis.^[1][2] The underlying mechanism is that of an autoimmune disease with antibodies binding to IgA and forming immune complexes.^[1] These complexes build up and result in inflammation of the kidneys.^[1] The process may be triggered by an infectious disease.^[2] Diagnosis is suspected based on blood and urine tests and confirmed by a kidney biopsy.^[1]

While there is no cure, treatment often involves medication to suppress the immune system such as corticosteroids or cyclophosphamide.^[1] Other measures may include blood pressure control such as with ACE inhibitors and the use of diuretics to remove excess fluids.^[1] A kidney transplant may be an option in those with kidney failure.^[2] Outcomes are often good.^[2]

IgA nephropathy is one of the most common kidney diseases.^[1] Onset is generally in late childhood to late 30s.^[1] Males are more commonly affected than females.^[1] Asian and white people are more commonly affected.^[1] The condition was first clearly described by Jean Berger, a Fence Pathologist, in 1968.^[2][3]

Signs and symptoms

The classic presentation for the non-aggressive form (in 40–50% of the cases) is episodic hematuria, which usually starts within a day or two of a non-specific upper respiratory tract infection (hence synpharyngitic), as opposed to post-streptococcal glomerulonephritis, which occurs some time (weeks) after initial infection. With both aggressive and non-aggressive Berger's disease loin pain can also occur. The gross hematuria may resolve after a few days, though microscopic hematuria will persist, it is however more common with aggressive Berger's disease for gross hematuria to persist rather than microscopic hematuria. Renal function usually remains normal with non-aggressive Berger's disease, though rarely acute kidney failure may occur (see below). This presentation is more common in younger adults.

The following is a basic list of symptoms taken primarily from Mayo clinic;

• Severe flank/abdominal pain
• High blood pressure
• Hematuria (gross, frank, microscopic)
• Compromised immune system
• Edema in hands and feet
• Cola- or tea-colored urine

A smaller proportion (20–30%), usually the older population, have microscopic hematuria and proteinuria (less than 2 gram/day). These patients may be asymptomatic and only picked up due to urinalysis. Hence, the disease is more commonly diagnosed in situations where screening of urine is compulsory (e.g., schoolchildren in Japan).

Very rarely (5% each), the presenting history is:

• Nephrotic syndrome (3–3.5 grams of protein loss in the urine, associated with a poorer prognosis)
• 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)

A variety of systemic diseases are associated with aggressive IgA nephropathy (Berger's disease) such as liver failure, cancer, celiac disease, systemic lupus erythematosus, rheumatoid arthritis, heart failure, reactive arthritis, ankylosing spondylitis and HIV. Diagnosis of Berger's disease 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. Some HLA alleles have been suspected along with complement phenotypes as being genetic factors. Non-aggressive Berger's disease may also be associated with any of the above systemic diseases, however this is rare.

Cause

Pathophysiology

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 were observed. Correspondingly, HSP nephritis has a higher frequency of glomerular staining for fibrin compared with IgAN, but with an otherwise similar immunofluorescence profile.^[4]

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 serine and threonine residues in a special proline-rich hinge region. Aberrant glycosylation of IgA appears to lead to polymerisation of the IgA molecules in tissues, especially the glomerular mesangium.^[5] 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.^[6] 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 synthesis and binding of antibodies against IgA1 are required for immunoglobulin complexes to form and accumulate in glomeruli.^[7]

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.

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. 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, 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. 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 and eye problems.

Other blood tests done to aid in the diagnosis include CRP or ESR, complement levels, ANA, and LDH. Protein electrophoresis and immunoglobulin levels can show increased IgA in 50% of all patients.

Treatment

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 kidney failure and failure of other major organs. 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, cyclophosphamide, Isotretinoin 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. These studies hardly produce statistically significant evidence regarding the heterogeneity of IgA nephropathy patients, the diversity of study treatment protocols, and the length of follow-up.

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.^[8] 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.^[9]

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 6 months regimen of steroids in addition to other medications may lessen proteinuria and preserve renal function.^[10] 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 & 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.^[11] 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 slight reduction of progression to kidney failure, without, however, reducing proteinuria in a subset of patients with high risk of worsening kidney function.^[12] However, these results have not been reproduced by other study groups and in two subsequent meta-analyses.^[13][14] 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 kidney 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.^[15]

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 kidney failure.

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 the 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%. A confounding factor in this analysis is the existing policy of screening and use of kidney 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 observed incidence of IgA nephropathy in those countries.

History

Doctor Jean Berger

The senior William Heberden first described the disease in 1801 in a 5-year-old child with abdominal pain, hematuria, hematochezia, and purpura of the legs.^[16] In 1837, Johann Lukas Schönlein described a syndrome of purpura associated with joint pain and urinary precipitates in children. Eduard Heinrich Henoch, a student of Schönlein's, further associated abdominal pain and renal involvement with the syndrome. In 1968, Jean Berger (1930–2011), a pioneering French nephrologist, with co-author, the electron microscopist Nicole Hinglais, was the first to describe IgA deposition in this form of glomerulonephritis and therefore it is sometimes called Berger’s disease.^[17]

References

External links

• IGA Nephropathy Archived 2021-01-22 at the Wayback Machine on National Institute of Diabetes and Digestive and Kidney Diseases