Pediatric IgA Nephropathy 

Idiopathic immunoglobulin A (IgA) nephropathy, often termed Berger nephropathy, was first described by Berger and Hinglais in 1968, based on the finding of predominant IgA deposition in the mesangium with a mesangial proliferation and clinical features that spanned the spectrum from asymptomatic hematuria to rapidly progressive glomerulonephritis.

IgA nephropathy is the most common cause of primary glomerulonephritis throughout the developed world.^[1] Although it can present at any time, the peak incidence of disease is in the second and third decades of life. A male-to-female ratio of 2:1 is observed in North American and Western European populations, although this difference is not observed among populations in the Pacific.

IgA nephropathy occurs with greatest frequency in Asians and whites and is relatively rare in blacks. In a Chinese study, IgA nephropathy constituted 45% of all cases of primary glomerulonephritis.^[2] However, IgA deposits may also be seen on kidney biopsy findings in individuals with no evidence of renal disease. The reported incidence rate of mesangial IgA deposition in apparently healthy individuals is 3-16%. These cases had no clinical features of nephritis, but their renal biopsy findings were consistent with IgA nephropathy.

Spontaneous remission has been reported in children and adults. Secondary IgA nephropathy is also associated with various underlying disease processes. It was initially considered a benign condition, but extended follow-up indicates that IgA nephropathy does lead to significant kidney damage and progressive disease develops in 20–30% of children 15–20 years after disease onset. Advanced age, hypertension, proteinuria, and impaired renal function at presentation are poor prognostic indicators.

Forty years after its first description, the pathogenesis of IgA nephropathy is now becoming more clear. The pathogenesis of IgA nephropathy is the mesangial deposition of IgA (see image below), which is predominantly polymeric IgA of the IgA1 subclass (polymeric IgA1-containing J chain). Co-deposits of immunoglobulin G (IgG) and complement C3 are also commonly observed and may contribute to disease severity. The characteristic pathologic findings on immunofluorescence microscopy are granular deposits of IgA and C3 in the glomerular mesangium. The detection of IgA immune complexes from circulation suggests that this disease is the result of the deposition of circulating immune complexes.

Synthesis and release of IgA immune complexes into the circulation with chemical and biological characteristics that favor mesangial deposition

The ability of the reticuloendothelial system to effectively remove potentially pathogenic IgA immune complexes

The mesangial cell affinity and reaction to mesangial IgA accumulation

Inherent tendency of the kidney to respond to injury by mounting a response favoring progressive renal injury with glomerulosclerosis and interstitial fibrosis, rather than resolution of inflammation without these sequelae

Abnormality of glycosyltransferases, genetic mutation, and immunologic disorder were involved in the aberrant glycosylation of IgA1, which was recognized as the key etiopathogenesis of IgA nephropathy. However, the exact source and the pathogenic mechanism of aberrantly glycosylated IgA1 remain obscure.^[3]

Recurrence of IgA nephropathy has been reported in allograft, and rapid disappearance of IgA deposits is observed when kidneys with IgA deposits are transplanted in a patient without IgA nephropathy.

IgA is a major serum immunoglobulin and the predominant antibody class in the external secretions that bathe mucosal surfaces. This plays a key role in immune protection. Indeed, the body expends considerable energy in producing IgA, such that the daily production of IgA exceeds that of all the other antibody classes combined.

IgA, at concentrations of about 2-3 mg/mL, is the second most prevalent antibody in serum after IgG, which is normally present at about 12 mg/mL. Because serum IgA is metabolized 5 times faster than IgG, the production rates of serum IgA and IgG must be similar. Serum IgA is predominantly monomeric in nature; the secretory IgA (S-IgA) is chiefly polymeric, comprising mainly dimeric forms of IgA containing the J (joining) chain. S-IgA serves various functions to protect the vast surface area (approximately 400 m²) occupied by mucosal surfaces, such as the linings of the respiratory, GI , and genitourinary tracts. As the major class of antibody present at these sites, S-IgA can be considered an important first line of defense against many invading pathogens.

In humans, 2 subclasses of IgA (termed IgA1 and IgA2) are recognized, from a separate gene origin. Numerous sequence differences are found in their heavy chain constant regions (ie, C1, hinge, C2, and C3). A major difference between the subclasses lies in the hinge region, which is greatly extended in IgA1. Two allotypic variants of IgA2, named IgA2m(1) and IgA2m(2), have been well characterized. Their heavy chain constant region sequences differ at numerous points along their length. The most notable difference is that although IgA2m(2) has the disulphide bridges linking light and heavy chains typical of most immunoglobulins, these are generally lacking in IgA2m(1). Instead, the light chains bond to each other, and the association with the heavy chains is stabilized through noncovalent interactions.

Early electron microscopy studies provided the first insights into the shape and size of the different forms of IgA. More recently, molecular models for human IgA1 and IgA2m(1) based on radiographic and neutron scattering data have been generated. IgA1 may have a more extended reach than IgA2m(1) because the models predict that the tips of the Fab arms (ie, antigen binding sites) of IgA1 can be spaced at much greater distances apart than those of IgA2m(1). Hence, IgA1 may be able to simultaneously interact with 2 antigen molecules, separated by a considerable distance, whereas IgA2m(1) may have a more limited capability in this respect. Such a capacity may afford IgA1 advantages in higher avidity recognition of repeated antigenic structures spaced along the surface of certain pathogens.

S-IgA

The IgA patterns of external secretions are characterized by secretory IgA in saliva, tears, bile, and urine. IgA is also found in nasal, tracheobronchial, intestinal, and cervical fluids. Most IgA molecules in external secretions are present as dimers composed of 2 7S IgA monomers plus two other non-Ig proteins, the J chain and secretory component (molecular weight, 71,000).

IgA is the most abundant immunoglobulin in the body; it is chiefly concerned with mucosal defense. IgA is produced by plasma cells in the mucosa and by bone marrow cells. The mucosal immune system synthesizes polymer IgA (pIgA) and transports it into mucosal fluid. The secretory component remains attached to the pIgA. Plasma cells only assemble pIgA. Both subclasses of IgA (ie, IgA1, IgA2) are present in mucosa.

The process begins with the accumulation of IgA, predominantly IgA1, in renal mesangial cells. Glycosylation and the size of IgA1 are essential for the interaction with mesangial receptors in IgA nephropathy. IgA1 contains a J chain but no secretory component. IgA nephropathy is often assumed to be an immune complex disease because similar patterns of mesangial immunoglobulin deposition can be induced by the infusion of preformed antigen-antibody complexes. Deposition of IgA immunoglobulin leads to cytokine release, mesangial cell proliferation, and the activation of the complement system via the alternative pathway. Ultimately, the glomerular filtering surface is damaged and reduced, and renal failure ensues.

The fact that polymeric IgA1 is usually derived from the mucosal immune system, is associated with IgA nephropathy, and affects the respiratory or GI tract suggests that IgA nephropathy is a disease of the mucosal immune system. This concept was supported by the finding of immunoglobulin antibodies in dietary antigens or various infectious agents, both viral and bacterial, in some patients with IgA nephropathy. Additionally, it was supported by the clinical observation that some patients with IgA nephropathy, the hematuria increases acutely at the time of upper respiratory tract or gastrointestinal infection.

Regardless of the mechanism that leads to the increased deposition of IgA or IgA-containing immune complexes in the glomeruli, the mechanisms responsible for the glomerular injury remain poorly understood. Despite the demonstration of a specific IgA receptor on mesangial cells and in the glomerulus of patients with IgA nephropathy, studies of the expression of Fc alpha R on peripheral blood mononuclear cells and granulocytes led to conflicting results. IgA nephropathy may be linked to the expression of an IgA nephropathy specific variant of Fc alpha R (receptor) on monocytes. The role, if any, of Fc alpha R in the pathogenesis of IgA nephropathy remains to be elucidated.

IgA nephropathy and Henoch-Schönlein purpura (HSP)

IgA nephropathy and HSP share many morphologic and immunopathologic features. The most striking similarities between IgA nephropathy and HSP nephropathy (HSN) are mesangial IgA deposition, elevated serum IgA level, and IgA circulating immune complexes. The glomerular changes (diffuse or focal mesangial proliferation) in HSN are essentially the same as those in IgA nephropathy. An infective episode precedes HSN in 30-50% of patients, and presence of Haemophilus influenza antigen in the glomerular mesangium and the presence of IgA antibody against H Influenza in sera has been reported in the patient with HSN.

The presence of antineutrophil cytoplasm antibodies (ANCA) was proposed as a marker of HSN to distinguish HSN from IgA nephropathy. Both have broadly similar geographic distributions and are rare in black persons. Coexistence in different members of the same family have been reported. Despite these similarities, the 2 conditions are clinically different, and the pathogenesis is not clear. HSN is an acute condition, with a glomerular lesion, and mostly nonprogressive after the onset. Meanwhile, IgA nephropathy is a chronic progressive lesion, which may eventually lead to renal failure. IgA nephropathy has a male predominance. HSP occurs mostly in young children and is rare in adults, whereas IgA nephropathy mainly occurs in older children and young adults.

Oxford classification of IgA nephropathy

A Working Group of the International IgA Nephropathy Network and the Renal Pathology Society have developed a consensus on the pathologic classification of IgA nephropathy.^[4] The goal of the new classification was to identify specific pathological features that more accurately predict risk of progression of renal disease in IgA nephropathy. Clinical data and adequate renal biopsy material from 265 patients with IgA nephropathy were collected from 8 countries on 4 continents. Five centers from Asia, 6 from Europe, 2 from United States, 1 from South America, and 2 multicenter networks (Canada and the United States) participated in the study. The proportion of children was similar in each continent (approximately 30%). These patients were followed for a median of 5 years.

Several pathologists identified histologic variables by repeated analysis of biopsies that were consistently interpreted with a high degree of reproducibility. The following variables were identified that correlated with renal outcomes:

• Mesangial hypercellularity (see image below)
• Segmental glomerulosclerosis
• Endocapillary hypercellularity
• Tubular atrophy/interstitial fibrosisGlomerulus with mesangial hypercellularity and intact capillary loops. Trichrome Stain, original magnification 400x. Image courtesy of Patrick D Walker, MD.

Based on these data, the committee developed the numerical scores on the presence or absence of these variables. The suggested scoring system is as below:

Mesangial cells are counted per mesangial area and a score of 0-3 is assigned for each glomerulus. A score of 0 indicates that fewer than 4 mesangial cells are present per mesangial area; a score of 1 indicates that 4-5 mesangial cells are present per mesangial area; a score of 2 indicates that 6-7 mesangial cells are present per mesangial area; and a score of 3 indicates that greater than 8 mesangial cells are present per mesangial area. Scores obtained for all glomeruli are averaged, and the resulting assigned hypercellularity score is either M0 if the mean score is less than 0.5 or M1 if the mean score is greater than 0.5.

Segmental glomerulosclerosis is defined as present (S1) if any part of the glomerular tuft is involved in sclerosis or absent (S1) if no segmental glomerulosclerosis is present.

Endocapillary hypercellularity is defined as present (E1) if hypercellularity is present within the glomerular capillary lumina and results in narrowing of the lumina or absent (E0) if no hypercellularity is present within lumina.

The percentage of the cortical area involved by tubular atrophy or interstitial fibrosis is quantitated. A score of T0, T1, or T2 is given if the percentage of involved cortical area is 0-25%, 26-50%, or more than 50%, respectively.

Biopsies with fewer than 8 glomeruli should be considered of uncertain value for prognosis.

Frequency

United States

IgA nephropathy accounts for 5-10% of all primary glomerular diseases occurring in the United States. The prevalence of IgA nephropathy in the general population has been estimated to be about 25-50 cases per 100,000 population. Almost 5% of all biopsied patients have at least some IgA deposits in their glomeruli. The incidence of end-stage renal disease (ESRD) due to IgA nephropathy was 5.5 cases per million population per year; about 8.4 cases for males and 2.7 cases for females.

International

IgA nephropathy has been diagnosed worldwide, but its prevalence in different countries varies. In Pacific countries, particularly in Japan, it accounts for approximately 50% of all primary glomerular diseases. In Europe, it is responsible for 20-30%. The explanation of this apparent variability is uncertain but may be related, in part, to differing indications for renal biopsy in different centers. High incidence rates are reported in Asia, France, Italy, Finland, and southern Europe. Genetic and environmental factors may contribute to geographic differences in prevalence. Population studies in Germany and France have calculated an incidence of 2 cases per 10,000, although autopsy studies performed in Singapore suggest that 2-4.8% of the population may have IgA deposition in their glomeruli.

Mortality/Morbidity

Although IgA nephropathy was thought to carry a relatively benign prognosis, an estimated 1-2% of all patients with IgA nephropathy develop end-stage renal failure each year from the time of diagnosis. In a study of 1900 patients derived from 11 separate series, the long-term renal survival was estimated to be 78-87% within a decade of presentation. Similarly, European studies have suggested that renal insufficiency may occur in 20-30% of patients within 2 decades of the original presentation.

In a study from Hong Kong, patients with mild IgA nephropathy were prospectively followed.^[5] Significant proteinuria or renal insufficiency was found in numerous patients, suggesting that a significant risk of progression is present, even in patients who present with milder forms of disease.

Several studies have assessed features that predict a poor prognosis. Sustained hypertension, persistent proteinuria (especially proteinuria >1 g), impaired renal function, and the nephrotic syndrome constitute poor prognostic markers.

Typically, mortality associated with IgA nephropathy is secondary to renal failure or its complications. Morbidity may be subsequent to hypertension, electrolyte abnormalities, or other consequences of reduced renal function.

Familial IgA nephropathy has an increased risk of end-stage renal disease.

Race

The distribution of IgA nephropathy varies in different geographic regions throughout the world. It is the most common form of primary glomerular disease in Asia, accounting for as much as 30-40% of all biopsy findings, for 20% of biopsies in Europe, and for 10% of all biopsies performed for glomerular disease in North America. The reason for this wide variance in incidence is partly attributable to indications for renal biopsy in Asia compared to those in North America. In the United States, incidence of IgA nephropathy is increased in children who are Asian or white; incidence is lowest in blacks.

Sex

Incidence is higher in males than in females. Male-to-female ratios of 2:1 and 6:1 have been reported.

Age

IgA nephropathy occurs in persons of all ages but is still most common in the second and third decades of life and is much more common in males than females. IgA nephropathy is uncommon in children younger than 10 years. In fact, 80% of patients are between the ages of 16-35 years at the time of renal biopsy.