IgA nephropathy

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Ali Poyan Mehr, M.D. [2] Associate Editor(s)-in-Chief: Olufunmilola Olubukola M.D.[3]

IgA nephropathy (Berger disease) was first described by Jean Berger, a pathologist, and Nicole Hinglais, an electron microscopist, in 1968 in France.

• In 1968, IgA nephropathy was first described by Jean Berger, a pathologist, and Nicole Hinglais, an electron microscopist, in France.^[1][2][3][4]

• IgA nephropathy was originally described by Berger and Hinglais in 1968. In the original one-page article titled “Les depots intercapillaires d’IgA-IgG” in the “journal d’Urologie-Nephrologie”, the authors described the renal disease under light microscopy showing focal and segmental mesangial proliferation with expansion of the matrix. Under electron microscopy, they noted the predominance of IgA deposits in the renal mesangium that were associated with the presence of less significant presence of IgG and C3.
• In 1969, following the first description of IgA nephropathy, the association of IgA nephropathy with Henoch-Schönlein purpura was described by Berger.^[1]

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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: Olufunmilola Olubukola M.D.[3]

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.

IgA nephropathy may be classified according to its association to other pathology or by its histological features.

IgA nephropathy may be classified according to its association to other pathology (or lack there of) as follows:

When IgA nephropathy occurs alone, it is called “primary IgA nephropathy”. It is thus not secondary to any chronic concomitant disease. Before the diagnosis of primary IgA nephropathy is made, secondary causes need to be ruled out.

When IgA nephropathy occurs secondary to other chronic or systemic diseases, it is called “secondary IgA nephropathy”. Secondary causes of IgA nephropathy should be ruled out because secondary causes may alter the management plan and probably the prognosis too.

The pathologic classification of IgA nephropathy has been developed by the International IgA Nephropathy Network together with the Renal Pathology Society. This classification is called “The Oxford classification of IgA nephropathy”. This classification was done after a 5 years retrospective study on clinical data and kidney biopsies were obtained from 265 patients and multiple pathohistological analyses were done on the kidney specimens ^[1].

• IgAN is then histologically classified as:
  • Mesangial hypercellularity
  • Segmental glomerulosclerosis
  • Endocapillary hypercellularity
  • Tubular atrophy/interstitial fibrosis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Rim Halaby, M.D. [2];Olufunmilola Olubukola M.D.[3]

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.

• 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 ^[1].
• These genetic associations are poorly studied and are largely inconclusive. There are ongoing studies in this field.
• Primary IgA nephropathy is caused by a genetic predisposition in patients who typically present immediately following a respiratory or gastrointestinal tract infections. The environmental exposure to these infectious agents may thus facilitate the subsequent pathogenesis of the disease.

The most common etiologies associated with glomerular IgA deposits and thus secondary IgA nephropathy include:

• Liver cirrhosis^[2]

• Celiac disease^[2]

• HIV infection^[2]

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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: Mehrian Jafarizade, M.D [3], Syed Hassan A. Kazmi BSc, MD [4]

The various types of glomerular diseases should be differentiated from each other based on associations, presence of pitting edema, hematuria, hypertension, hemoptysis, oliguria, peri-orbital edema, hyperlipidemia, type of antibodies, light and electron microscopic features.

The various types of glomerular diseases should be differentiated from each other based on associations, presence of pitting edema, hematuria, hypertension, hemoptysis, oliguria, peri-orbital edema, hyperlipidemia, type of antibodies, light and electron microscopic features. The following table differentiates between various types of glumerular diseases:

Some infectious diseases such as HIV, HBV, HCV, syphilis, leprosy, malaria, and schistosomiasis may cause glomerular diseases.

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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: Olufunmilola Olubukola M.D.[3]

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.

• IgA nephropathy is currently the most common cause of primary glomerulonephritis globally. ^[1]
• IgA nephropathy is the most common primary chronic glomerulonephritis in the developed world.
• IgA nephropathy comprises approximately 10% of all biopsy-proven glomerulonephritis in USA, 20% of those in Europe and 40-50% of those in Asia.^[2]
• 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.

• In 2013, the incidence of IgA nephropathy was estimated to be 3.9–4.5 cases per 100,000 individuals in Japan.^[3]

• IgA nephropathy is found more commonly in Asians, Caucasians and people of Eastern Europe. It is very rare in Blacks and people of African descent.

• IgA nephropathy seems to be more common among males with a 2:1 male to female ratio for both children and adults.^[4][5]
• The studies from Japan report an equal male to female ratio.^[6]

• IgA nephropathy may present at any age although, it can occur in childhood.
• IgA nephropathy is often found mostly in adult males in the second to third decade of life.
• It is a frequently diagnosed glomerular disease in both the pediatric and the adult population.
• The median age ranges between 30-40 years. Recently, IgA Nephropathy has shown an increase in incidence among patients in older age groups.^[7]
• Although the classical presentation of IgA nephropathy is gross hematuria in a young male patient following an upper respiratory tract infection, such findings are in fact only seen in 30-40% of the patients.^[7] Atypical presentations are more common among older patients.
• It is also noteworthy, that some studies have shown incidence of IgA nephropathy in about 3 -16% healthy individuals ^[8].
• The renal biopsy of the healthy individuals showed evidence of immunogenic IgA deposit in the renal glomeruli without any evidence of kidney disease or systemic manifestation.

• IgA nephropathy is highly prevalent in the Pacific Rim in Europe and North America^[7] and in the far East Asia, namely China and Japan.^[9]

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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: Olufunmilola Olubukola M.D.[3]

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.

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.

Broadly, the only risk factors that seem to be associated with the development of IgA nephropathy are:

• Male predominance was found to be associated in some studies, especially in Northern America with a 2:1 male to female ratio.^[1][2]

• 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.^[3]
• Blacks have a much less rate of diagnosis.^[4]

• Up to 40% of immediate family members have elevated levels of aberrant IgA1 levels and approximately 5% of relatives will manifest IgA nephropathy.^[5][3]

• The genetic susceptibility plays the most and perhaps the only important role in the development of IgA nephropathy.
• The role of genetics has been well established in the pathogenesis of IgA nephropathy.
  • The most common mode of inheritance is autosomal-dominant pattern with incomplete penetrance.^[6]
  • There is an emerging observation that galactose-deficient IgA1 immunoglobulin formation is in fact a genetic trait in specific populations, ethnicities, and geographical locations such as Pacific Rim and Asia.^[3]
  • It is much less frequently observed in African populations.^[4]

• Further evidence from studies that evaluate the diagnosis of IgA nephropathy in relatives reveals that not only 90% of patients with IgA nephropathy have high circulating levels of IgA1.
• 30-40% of relatives of patients with IgA nephropathy have elevated levels of IgA1.
  • Observational studies show that relatives of IgA nephropathy almost never have clinical forms of IgA nephropathy or renal injury except in 5% of the cases^[5][3], which suggests environmental influences and further emphasizes the multi-hit pathogenesis.^[7][5]

• IgA nephropathy does not seem to be inherited by simple Mendelian genetics.
• Major histocompatibility complex (MHC) DQ is likely to be involved, according to a study on patients with white European ancestry.
• Furthermore, studies enrolling Chinese, African, and European patients showed involvement of the same loci even among patients of different ethnicities.^[8]

A total of 5 loci are significant in IgA nephropathy:

• 3 loci on 6p21 encoding components of MHC I and MHC II response

• 1 locus on 1q32 in the cluster of genes encoding complement factor H (CFH) that mediates the activation of the alternative complement pathway

• 1 locus on 22q12 encoding oncostatin M and leukemia inhibitory factor
• Conversely, deletion of CFHR1 and CFHR3 reduced the risk of IgA nephropathy by 30%.^[5]

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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: Olufunmilola Olubukola M.D.[3]

According to the National Kidney Foundation guidelines for glomerulonephritis, screening is currently not recommended for IgA nephropathy.

According to the National Kidney Foundation guidelines for glomerulonephritis, screening is currently not recommended for IgA nephropathy.^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rim Halaby, M.D. [2]

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.

Complications of IgA nephropathy are generally those of renal injury.^[1][2][3]

• Hypertension
• Nephritic syndrome

• Nephrotic syndrome

• Acute kidney injury

• Chronic kidney disease

• End-stage renal disease

• Hypercholesterolemia

IgA nephropathy follows an unpredictable clinical course with debatable prognostic factors. Although considered a benign disease in comparison to other forms of glomerulonephritis, new data show that up to 20-30% of patients with IgA nephropathy progress to ESRD after 10 years.^[1] It is important, however, to note that experts concede that the true prognosis of IgA nephropathy is poorly established because the diagnosis by biopsy is often made late during stage 3-4 chronic kidney disease.^[3] The approximately 10-year renal survival following diagnosis ranges between 67-94%, based on the findings of 5 major trials from Germany, France, UK, Japan, and Australia and 1 meta-analysis from USA.^{[4][5][6][7][8]}

Several studies have analyzed factors associated with prognosis of IgA nephropathy. In 2011, Berthoux and colleagues established 3 main factors that have been attributed to be the core predictors of outcome when studying 332 patients with IgA nephropathy over 13 years^[9]:

Proteinuria is the most important prognostic factor with a “dose-dependent” effect^[10]

In 2011, Berthoux et al. calculated absolute renal risk (ARR) of dialysis or death.^[9] The absence of all 3 risk factors was associated with a 96% prediction of survival without hemodialysis.^[9] As ARR increased, survival prediction decreased, where the presence of all 3 risk factors was associated with only 36% prediction of survival without the need for dialysis.^[9]

In one major meta-analysis that involved a database of 148 patients with IgA nephropathy between 1973 and 1995, Radford and colleagues^[3] suggested a “glomerular score” based on previous findings from the literature that consists of the summation of 6 components:

• Mesangial hypercellularity

• Mesangial matrix increase

• Glomerular sclerosis

• Capillary narrowing or disruption

• Cellular crescents

• Fibrous adhesions

Observational, cross-sectional, and cohort studies to date have shown the following data to be significantly associated with progression of IgA nephropathy into ESRD and worse outcome. However, the significance of the following is variable and has not been consistent in the literature.

Genetic:

• D or DD allele of insertion/deletion (I/D) polymorphism of angiotensin-converting enzyme (ACE) gene^[11]

Clinical:

• Hypertension^[3][12]

• Smoking

• Metabolic Syndrome

Biochemical:

• Elevated serum creatinine levels at diagnosis^[3]

• Proteinuria^[3][12]

• Persistence of microscopic hematuria^[3]

• Hypertriglyceridemia^[12]

• Hyperuricemia^[12]

• Anemia^[13]

• Hypoalbuminemia^[13]

Histopathological:

• Abundance of crescent formation^[14][15]

• Glomerulosclerosis^{[16][4][5][6][17][7][8]}

• Interstitial fibrosis and expansion^{[16][4][17][15]}

• Mesangial hypercellularity and diffuse mesangial proliferation^[16][17][18]

• Tubular atrophy

Age remains a controversial predictor of outcome for patients with IgA nephropathy. While some studies showed that younger age is associated with worse outcomes^[3], these findings were not consistent in the literature and at times, completely opposing.^[16][4]

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