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IgA Glomerulonephritis

Bergers Disease

IgA glomerulonephritis is caused by glomerular deposition of immune complexes that contain abnormal immunoglobulin A. Most cases follow a benign, slowly progressive course, but patients diagnosed with severe IgA glomerulonephritis may eventually suffer from renal failure.


Presentation

Clinical presentation varies largely and patients may remain asymptomatic for years. Most patients eventually seek medical attention during periods of macroscopic hematuria. In fact, this may be one of the very few symptoms that manifest in the case of mild IgA-GN. Urine analysis may reveal microscopic hematuria in episodes of apparent freedom of symptoms, but in some cases, urine analysis may be temporarily normal.

If queried accordingly, most patients report a recent infection of the upper respiratory tract, of liver, stomach or intestines. In most cases, such infections may still persist and cause additional complaints. Subclinical infections may also cause the onset of macroscopic hematuria. This sequence of events is likely to reoccur upon renewed infection and thus, IgA-GN patients may also present with recurrent spontaneously resolving hematuria. Urinary excretion of erythrocytes is generally noted within 48 hours after experiencing first symptoms of the underlying infectious disease. This is in contrast to post-streptococcal glomerulonephritis, which manifests more than one week after infections of the respiratory tract or several weeks after skin infection.

In rare cases, IgA-GN may progress rapidly. Affected individuals may present with symptoms provoked by renal insufficiency, i.e., with hypertension and renal anemia.

Rapidly Progressive Glomerulonephritis
  • We report a case of rapidly progressive glomerulonephritis with P-ANCA, with biopsyproven crescentic IgA glomerulonephritis in an 11-week pregnant woman who responded very well to cyclophosphamide and prednisone.[ncbi.nlm.nih.gov]
  • Rapidly progressive glomerulonephritis (RPGN) is a renal disease with an extensive differential diagnosis.[leprosy-information.org]
  • However, it can also present as rapidly progressive glomerulonephritis.[news-medical.net]
Intravenous Administration
  • The DIR was measured using two 120-min creatinine clearance values (before and after intravenous administration of 2 g/kg/min dopamine). Serum UA, triglycerides and cholesterol and urinary NAG (24 h) and protein and UA excretion were measured.[ncbi.nlm.nih.gov]
Abdominal Pain
  • We present the case of a 75-year-old Hispanic woman with known stage 3 chronic kidney disease, long-standing hypertension and type 2 diabetes mellitus who presented with right-sided abdominal pain and acute kidney injury, nephrotic range proteinuria with[ncbi.nlm.nih.gov]
  • pain, joint pain and nephritis; “secondary mesangial IgA glomerulonephritis” means predominant IgA mesangial deposits in the presence of clinical or laboratory evidence of any other associated systemic disease; “terminal event” means the proximate or[legislation.gov.au]
  • Eduard Heinrich Henoch, a student of Schönlein's, further associated abdominal pain and renal involvement with the syndrome.[en.wikipedia.org]
  • Haug Browse recently published Learning/CME Learning/CME View all learning/CME CME Partial Oral versus Intravenous Antibiotic Treatment of Endocarditis Case 4-2019: An 18-Year-Old Man with Abdominal Pain and Hematochezia Bridging the Gap Challenge Yourself[nejm.org]
Hypertension
  • Overall prevalence of hypertension (HT) was similar in IgA-GN and non-IgA-GN (38.7% vs 38.2%).[ncbi.nlm.nih.gov]
Arthralgia
  • Within 14 days of commencing rivaroxaban, he developed a non-blanching purpuric rash, nephrotic range proteinuria (4.1g in 24 hours), bilateral pitting lower limb oedema, bilateral flank pain, and constitutional symptoms (night sweats, myalgias, and arthralgias[anzsnasm.com]
  • However, immunoglobulin A–associated vasculitis is clinically distinct from IgA nephropathy, usually manifesting as hematuria, purpuric rash, arthralgias, and abdominal pain. Other serum immunologic tests are usually unnecessary.[merckmanuals.com]
  • The arthralgias commonly involve the joints of the lower extremities with less common involvement of upper extremity joints. Gastrointestinal symptoms include colicky abdominal pain, vomiting and/or bleeding and occur in 50-75% of patients.[propath.com]
  • […] known as S-H syndrome, S-H nephritis, anaphylactoid purpura, and rheumatoid purpura (in some texts the eponymous appears inverted: Henoch-Schönlein), is characterized by purpuric skin lesions (mainly on the lower extremities and buttocks), migratory arthralgias[kidneypathology.com]
Hematuria
  • The serum TNF-alpha level of IgA GN with macroscopic hematuria was significantly higher than that with microscopic hematuria.[ncbi.nlm.nih.gov]
  • Subclinical infections may also cause the onset of macroscopic hematuria. This sequence of events is likely to reoccur upon renewed infection and thus, IgA-GN patients may also present with recurrent spontaneously resolving hematuria.[symptoma.com]
Macroscopic Hematuria
  • We suggest that macroscopic hematuria of IgA GN was closely related to the serum TNF-alpha level.[ncbi.nlm.nih.gov]
  • A medical history of mucosal infections associated with recurrent macroscopic hematuria should prompt a strong suspicion for IgA-GN.[symptoma.com]
Microscopic Hematuria
  • There was no correlation in the severity of histological grade and clinical outcome between subjects with microscopic hematuria and those with microscopic hematuria and proteinuria nor between those with and without one or more episodes of macroscopic[ncbi.nlm.nih.gov]
  • Urine analysis may reveal microscopic hematuria in episodes of apparent freedom of symptoms, but in some cases, urine analysis may be temporarily normal.[symptoma.com]
Kidney Failure
  • […] 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[en.wikipedia.org]
  • In some cases kidney failure develops, leading to the question of dialysis and/or transplantation. What are the complications of IgA Nephropathy? High blood pressure may develop.[kidney.org.uk]
  • Some people leak blood in their urine without developing problems, some eventually achieve complete remission, and others develop end-stage kidney failure. No cure exists for IgA nephropathy, but certain medications can slow its course.[drugs.com]
  • Over time, some patients with IgAN slowly get worse until they reach kidney failure, If this occurs, you will need a kidney transplant or dialysis to stay alive.[kidney.org]
Flank Pain
  • Flank pain can occur. The hematuria resolves after a few days. These episodes occur on an irregular basis, and in most patients, this eventually stops (although it can take many years).[rxpgonline.com]
  • Flank pain and low-grade fever may accompany acute episodes. Other symptoms are usually not prominent.[merckmanuals.com]
  • Within 14 days of commencing rivaroxaban, he developed a non-blanching purpuric rash, nephrotic range proteinuria (4.1g in 24 hours), bilateral pitting lower limb oedema, bilateral flank pain, and constitutional symptoms (night sweats, myalgias, and arthralgias[anzsnasm.com]
  • pain, a presentation typical of younger Pts; older Pts tend to be asymptomatic and IN is detected by sediment and proteinuria Treatment ACE-inhibitors, corticosteroids, n-3 polyunsaturated fatty acids provided in dietary fish oil may slow progression[medical-dictionary.thefreedictionary.com]

Workup

A medical history of mucosal infections associated with recurrent macroscopic hematuria should prompt a strong suspicion for IgA-GN. Here, urine analysis is a first-line diagnostic measure that will reveal transient or persistent microscopic hematuria after spontaneous resolution of macroscopic hematuria. Dysmorphic red blood cells and cellular casts are frequently observed. Additionally, proteinuria can be detected and quantified by urine analysis.

Laboratory analysis of blood samples should be conducted to assess renal function; measurement of serum IgA concentrations may support a tentative diagnosis of IgA-GN but is neither a specific nor sensitive parameter. About half of all patients do not show increased levels of serum IgA and on the other hand, enhanced IgA concentrations may be detected in individuals infected with human immunodeficiency virus who never develop IgA-GN.

Maeda et al. reported the following criteria to be very helpful in IgA-GN diagnosis [11]:

  • Hematuria (> 5 erythrocytes in urinary sediments)
  • Persistent proteinuria (> 0.3 g/d)
  • Serum IgA levels > 30 g/l
  • Serum IgA/C3 ratio > 3

According to the authors, IgA-GN patients fulfill at least three of the aforementioned criteria.

Nevertheless, histopathological analysis of renal tissue samples is still considered the gold standard to confirm a tentative diagnosis of IgA-GN. Deposition of IgA immune complexes and mesangial proliferation are important findings, whereas type and extent of glomerular lesions may vary. IgA immune complexes are visualized by means of immunofluorescent staining. Of note, patients suffering from Henoch-Schönlein purpura may present identical renal lesions; it has even been suggested that both Henoch-Schönlein purpura and IgA-GN are merely different manifestations of a single disease [6].

Creatinine Increased
  • Cumulative Percentage of Patients with IgA Nephropathy Treated with Fish Oil or Placebo Whose Serum Creatinine Increased by 50 Percent or More during the Two-Year Treatment Period. The figure stops at 2.2 years.[doi.org]
  • This case corresponds to a 32-years-old woman with episodes of macrohematuria; in the last episode, when this biopsy was undertaken, she presented, in addition, serum creatinine increase.[kidneypathology.com]
Hepatocellular Carcinoma
  • A patient who developed crescentic IgA nephropathy following treatment with recombinant interleukin-2 (rIL2) and lymphokine-activated killer (LAK) cell therapy for hepatocellular carcinoma was reported.[ncbi.nlm.nih.gov]

Treatment

Causative treatment is not available and any therapeutic approach aims at reducing production of defective IgA, conserving renal function and counteracting complications of functional impairment of the kidneys. Patients whose serum creatinine levels are below 1.2 mg/dl and who excrete less protein than 0.3 g/d do not require specific treatment but should be monitored. If laboratory findings become worse, drug therapy should be initialized.

The following drugs may be applied:

  • Immunomodulatory compounds, mainly corticosteroids to reduce immunoglobulin production and allow for renal recovery.
  • Angiotensin-converting-enzyme inhibitors or angiotensin II receptor blockers to control hypertension.

In the case of renal failure, dialysis becomes necessary. In contrast, kidney transplants rarely resolve the problem of renal failure due to IgA-GN. Because IgA immune complexes are not formed in the kidneys but in peripheral circulation, IgA-GN patients who receive a kidney transplant are likely to suffer a relapse of glomerulonephritis [12]. In contrast, kidneys obtained from IgA-GN patients that don't show irreversible damage may be donated and it is to be expected that immune complex deposits diminish over time since the recipient's immune system does generally not produce abnormal immunoglobulins.

Only scarce evidence supports tonsillectomy as a therapeutic measure in IgA-GN patients [4]. This also applies for dietary supplementation with ω-3 polyunsaturated fatty acids and avoidance of gluten, meat and dairy products.

Prognosis

In general, IgA-GN is a slowly progressive nephropathy that requires minimal to none specific treatment and is associated with a good prognosis. Rapid progression has been observed, but rarely occurs.

About 10% of IgA-GN patients will require dialysis within 10 years of symptom onset and twice as many will depend on such therapy after 20 years. A variety of unfavorable prognostic factors has been identified, but they are all related to advanced renal damage and are thus not assessable during early stages of the disease. In detail, hypertension, elevated serum levels of urea and creatinine, low serum concentrations of albumin, severe proteinuria, and persistent microscopic hematuria have been associated with poor outcomes [10]. With regards to histopathological analyses, extensive mesangial proliferation (glomerular crescents), fibrotic remodeling and mast cell infiltration indicate severe kidney damage and an unfavorable prognosis.

Etiology

The main pathomechanism behind IgA-GN is the production of poorly galactosylated IgA that forms immune complexes which subsequently bind to mesangial cells and induce glomerulonephritis. Thus, etiologic studies have been conducted to clarify why affected individuals produce abnormal IgA and which conditions trigger an increase in serum levels of these defective antibodies.

With regards to the former question, genetic disorders have been related to IgA-GN. Immune complexes that bind to mesangial cells in patients suffering from this disease are of subclass IgA1. Several dozens of genes have been identified that may contribute to overproduction of IgA1 and aberrant glycosylation of these antibodies. Furthermore, IgA-GN patients may produce autoantibodies of type IgG that recognize defective IgA1 and cause the formation of immune complexes [3]. Soluble Fc receptor CD89 may also bind to galactose-deficient IgA1 and induce immune complex formation; this pathophysiological process may account for IgA-GN. Reports about the familial accumulation of IgA-GN support the hypothesis of gene defects predisposing for the disease [5].

Many case reports have been published that associate recent infections of the upper airways, of the gastrointestinal tract or liver with the onset of symptomatic IgA-GN. Infectious diseases of the respiratory and digestive tract pertain to the large group of mucosal infections and IgA1 is mainly produced in this type of disease. Thus, it is not surprising that an aggravation of IgA1-induced pathologies can be observed in patients who contracted such infections [4]. Of note, this also applies to predisposed patients who suffer from celiac disease and non-infectious liver disease.

Furthermore, patients suffering from autoimmune diseases like Henoch-Schönlein purpura (an IgA-mediated systemic vasculitis) and systemic lupus erythematosus (not typically associated with IgA disorders) have been diagnosed with IgA-GN [6] [7].

Epidemiology

IgA-GN may affect people of all races, both genders, and all age groups. However, the overall incidence of IgA-GN varies largely among populations of Asia, Europe, and America. About half of all renal biopsies taken in Asia test positive for IgA-GN and in Europe, analysis of one out of five renal tissue samples leads to the diagnosis of this disease. In contrast, IgA-GN is less often diagnosed in America.

Of note, school children are routinely screened for diseases of the urogenital system in determined Asian countries. If hematuria is detected upon urine analysis, further diagnostic measures are taken and consequently, renal biopsies are much more frequently realized than in Europe and America. This may introduce a bias that may at least partially account for higher prevalence rates observed in Asian populations. However, geographical differences may also be explained by the distinct prevalence of causative genetic disorders.

Independent of their country of residence, Blacks are least frequently affected by this form of glomerulonephritis [8].

In general, men are diagnosed with IgA-GN significantly more often than women. Male-to-female ratios may reach 5:1. Interestingly, this gender predilection seems to be inversed in Blacks.

An age peak of IgA-GN incidence can be observed during patient's second and third decade of life. Only isolated case reports exist about IgA-GN in patients younger than 10 years.

Sex distribution
Age distribution

Pathophysiology

The presence of IgA immune complexes in renal corpuscles has been related to kidney disease decades ago [2]. In recent years, intense research allowed shedding some light on the pathophysiological events leading to the formation and deposition of such immune complexes.

There are two subclasses of IgA, namely IgA1 and IgA2. In serum, IgA accounts for minor shares of total immunoglobulin concentrations. In contrast, these antibodies fulfill important functions in establishing mucosal barriers in the respiratory, gastrointestinal and urogenital tracts. They are produced by mucosal plasma cells and are actively transported into the lumen of the respective organ. Intermediate stages of B lymphocytes, so-called IgA-positive plasmablasts, can also be found in peripheral blood [9]. Serum levels of IgA, particularly of IgA1, may be increased in IgA-GN patients, but this is not a prerequisite for the development of the disease. In any case, IgA1 of IgA-GN patients are poorly galactosylated and seem to induce the production of glycan-specific anti-IgA1 autoantibodies. Both antibodies agglomerate and form immune complexes which reach glomeruli via the bloodstream. As has been indicated above, Fc receptor CD89 seems to be implied in IgA-GN pathogenesis, too. In its soluble isoform, this receptor may bind defective IgA1 and form immune complexes in the peripheral circulation. Contradictory results have been published regarding CD89 expression by mesangial cells, a theory that would explain why immune complexes don't deposit in other tissues. Of note, binding of immune complexes to mesangial cells may also be mediated by an as of yet unidentified receptor different from CD89.

Binding of immune complexes to mesangial cells induces production of cytokines, chemokines, and complement 3(C3) and induces mesangial proliferation, the histopathological hallmark of IgA-GN. This leads to chronic glomerulonephritis and progressive reduction of the glomerular filtration rate.

Prevention

In some Asian countries, school children are screened for urogenital disease by means of urine analysis. This way, microscopic hematuria, and proteinuria are detected early and the corresponding diagnostic workup can be initiated. The efficiency of such measures in regions of lower disease prevalence is questionable, though.

Summary

The medical term glomerulonephritis refers to an inflammation of renal corpuscles and IgA glomerulonephritis (IgA-GN) is the most common type of primary glomerulonephritis [1]. It may also be referred to as IgA nephropathy, IgA nephritis, and, less frequently, Berger disease. The latter designation honors Jean Berger, a French nephrologist who first described this entity in 1968 [2].

Over the course of the disease, immune complexes formed by abnormal immunoglobulin A (IgA) and autoantibodies against defective IgA bind to mesangial cells and induce mesangial proliferative glomerulonephritis [3]. According to current knowledge, genetic disorders account for the production of aberrantly glycosylated IgA, subclass 1. IgA-GN patients may report recent infections of the upper respiratory tract [4], but gastrointestinal and hepatic infectious diseases have also been related to the onset of IgA-GN. The disease follows a slowly progressive course, with hematuria being the most common symptom. Mild IgA-GN does not provoke additional complaints and may not require specific therapy. In moderate to severe cases, renal function impairment may lead to considerable reduction of the glomerular filtration rate, elevations in serum concentrations of urea and creatinine, and hypertension.

Diagnosis is based on clinical presentation, urine analysis, and renal biopsy. The latter is required to confirm a tentative diagnosis of IgA-GN; detection of mesangial deposition of IgA immune complexes and mesangial proliferative glomerulonephritis are important findings. Treatment aims at controlling the underlying disease, diminishing IgA and autoantibody production and compensating for renal function impairment. To this end, immunomodulatory compounds and anti-hypertensive drugs may be applied. A minor share of patients will eventually require dialysis despite compliance with therapeutic regimes.

Of note, other forms of primary glomerulonephritis are post-streptococcal glomerulonephritis (or, more generally expressed, post-infectious glomerulonephritis), membranoproliferative glomerulonephritis and crescentic glomerulonephritis.

Patient Information

IgA glomerulonephritis (IgA-GN) is the medical term for an inflammation of renal corpuscles due to pathological deposition of IgA immune complexes.

The human body is confronted with infectious agents and a lot of other antigens that may enter via the respiratory, gastrointestinal or urogenital tract. The mucosal membranes of these organ systems dispose of antibody-producing plasma cells that contribute to the mucosal barrier and these antibodies are of type A, i.e., they are designated immunoglobulin A (IgA).

Some people produce defective IgA that does induce an immune response itself. The patient's immune system produces anti-IgA antibodies that bind to defective IgA and thus form so-called immune complexes. These complexes circulate through the body and finally reach the kidneys. The aforementioned immune complexes cannot be excreted but bind to determined cells of the glomeruli and induce an inflammation, namely IgA-GN.

Because (defective) IgA production is induced by mucosal infections, symptoms of IgA-GN typically occur one or two days after catching a cold or contracting other respiratory or gastrointestinal infections. Chronic diseases of those organ systems may also cause IgA-GN symptom onset. Generally, patients will merely note blood particles in their urine. This is referred to as hematuria. Additional symptoms are rare. Over the course of the disease, periods of hematuria will alternate with episodes of apparent freedom of symptoms.

In mild cases, no specific treatment is required. However, the disease may follow a progressive course and may lead to considerable renal function impairment that does require drug therapy and possibly dialysis.

References

Article

  1. Couser WG. Pathogenesis and treatment of glomerulonephritis-an update. J Bras Nefrol. 2016; 38(1):107-122.
  2. Berger J, Hinglais N. [Intercapillary deposits of IgA-IgG]. J Urol Nephrol (Paris). 1968; 74(9):694-695.
  3. Lai KN, Tang SC, Schena FP, et al. IgA nephropathy. Nat Rev Dis Primers. 2016; 2:16001.
  4. Meng H, Ohtake H, Ishida A, Ohta N, Kakehata S, Yamakawa M. IgA production and tonsillar focal infection in IgA nephropathy. J Clin Exp Hematop. 2012; 52(3):161-170.
  5. Lavigne KA, Woodford SY, Barker CV, et al. Familial IgA nephropathy in southeastern Kentucky. Clin Nephrol. 2010; 73(2):115-121.
  6. Kamei K, Ogura M, Sato M, Ito S, Ishikura K. Evolution of IgA nephropathy into anaphylactoid purpura in six cases-further evidence that IgA nephropathy and Henoch-Schonlein purpura nephritis share common pathogenesis. Pediatr Nephrol. 2016; 31(5):779-785.
  7. da Silva LS, Almeida BL, de Melo AK, de Brito DC, Braz AS, Freire EA. IgA nephropathy in systemic lupus erythematosus patients: case report and literature review. Rev Bras Reumatol (Rio J). 2016; 56(3):270-273.
  8. Crowley-Nowick PA, Julian BA, Wyatt RJ, et al. IgA nephropathy in blacks: studies of IgA2 allotypes and clinical course. Kidney Int. 1991; 39(6):1218-1224.
  9. Macpherson AJ, McCoy KD, Johansen FE, Brandtzaeg P. The immune geography of IgA induction and function. Mucosal Immunol. 2008; 1(1):11-22.
  10. Tomino Y. Predictors of prognosis in IgA nephropathy. Kaohsiung J Med Sci. 2012; 28(10):517-520.
  11. Maeda A, Gohda T, Funabiki K, Horikoshi S, Shirato I, Tomino Y. Significance of serum IgA levels and serum IgA/C3 ratio in diagnostic analysis of patients with IgA nephropathy. J Clin Lab Anal. 2003; 17(3):73-76.
  12. Wyld ML, Chadban SJ. Recurrent IgA Nephropathy After Kidney Transplantation. Transplantation. 2016.

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Last updated: 2019-07-11 20:47