For over 40 years, IgAN has been recognized as a major cause of progressive glomerular disease. In 1987 IgAN was defined as the “commonest glomerulonephritis in the world” [7]. However, its prevalence varies considerably among countries, and it is influenced by sex and ethnicity. It is found more often in men and distinctly less in blacks [8]. Renal biopsy and Registry data of all primary glomerular diseases show that the prevalence of IgAN ranges from 20 % up to 50 % in Asia (45 % in China; nearly 50 % in Japan) and 20–40 % in Europe (37 % in Italy, 29 % in Romania, 19 % in Spain). Percentages as low as 2–4 % have been reported in some parts of the USA. However, a prevalence of over 35 % has been observed in American Indians in the Southwest and 14 % in young American Caucasians. In Australia, the general estimated prevalence is 12 %, but in Victoria, due to a relatively liberal policy of renal biopsy, the prevalence is higher, and the incidence is 87 cases per million per year [9].

Local indications for renal biopsy and health screening practices had influenced the epidemiologic data. Early studies carried out in 1975 reported rates of less than 5 % [10] in Great Britain, while 12 years later, Propper et al. reported that in Scotland, 37 % of patients affected by isolated hematuria had IgAN [11]. Based on autopsy studies on the general population, asymptomatic deposition of IgA is estimated at an average of about 10 % [12].

The majority of studies show a male predominance of at least 2:1 [13]. Unlike other glomerular diseases, IgAN and HSPN are uncommon in both African-Americans and in Africans [14]. Some authors have attributed this difference to a different structural property of IgA₂ according to different allotypes, i.e., A₂m(1) and A₂m(2). The A₂m(2) allotype that predominates in blacks is more resistant to cleavage and could provide a protective role against IgAN. Nevertheless, the IgAN clinical course in blacks does not differ significantly from what is observed in whites [15–18].

After the initial diagnosis of IgAN in identical twins in 1978 [19], scattered family studies and a number of studies on sporadic cases strongly suggested a genetic predisposition for at least some patients with IgAN and familial primary IgAN. The true frequency of familial IgAN remains uncertain because no serologic markers are currently available. Out of 269 cases from 48 families of IgAN patients, urinary abnormalities have been detected in 23 % [20]. In a second study, the same group examined a cohort of 110 patients with biopsy-proven IgAN and checked for both urinalysis and estimated renal survival. The 20-year renal survival rate from the apparent onset of the disease was significantly shorter in patients with familial (41 %) than sporadic IgAN (94 %). Furthermore, 15-year renal survival from the renal biopsy was reported to be significantly worse in familial disease: end-stage renal disease (ESRD) was present in 64 % of patients with familial and 8 % with sporadic IgAN [21]. Characterization of IgAN1 gene linked to IgAN in some Italian and American multiplex families has remained elusive [22].

A number of immunologic abnormalities suggesting a common genetic substrate affecting B-lymphocyte function in patients and their relatives have been reported: increased serum IgA, multimeric IgA and IgA rheumatoid factor, increased IgA1 production by peripheral blood mononuclear cells, detectable amounts of IgA–IgG complexes, and increased interleukin-2 and interleukin-4.

As regard to immunogenetics, IgAN was initially reported to be associated with HLA Bw35, but this association has not been confirmed. A benign course of IgAN has been associated with HLA DR4 in Japanese patients [23]. Because of the complex genetic architecture of IgAN, efforts to map disease susceptibility genes have not achieved definite results, and no causative mutations have been identified to date. Linkage analysis studies in families with IgAN have identified multiple loci and risk alleles, indicating that IgAN is likely a polygenic disease. These include a major disease locus (IgAN1) on chromosome 6q22–23 in Caucasian families [24] and a number of potentially significant gene polymorphisms, including uteroglobin [25], TGF beta [26], and atherosclerosis-associated genes [27]. A strong association with the HLA locus on chromosome 6p has been recently identified in a genome-wide analysis of familial and sporadic cases of IgAN in white Europeans [28].

Henoch-Schöenlein purpura (HSP) is the most common form of vasculitis in children (with an incidence of 10–20 cases per 100,000 children/year, <10-year-old in 90 % of cases). HLA B35 has been associated with an increased risk of nephritis. HLA DRB1*01, DRB1*11, and DRB1*14 also seem to increase susceptibility to glomerulonephritis.

Recent studies have focused on polymorphisms of genes encoding proinflammatory adhesion molecules associated with endothelial cell activation, TNF-α[alpha] , IL-1β[beta], IL-8, TGF-β[beta], and VEGF [29]. These studies are often limited by the relatively small cohorts.

HSP is a feature of the genetically determined familial Mediterranean fever (FMF) which is often observed in Israel and Turkey [30]. FMF is characterized by neutrophil activation and migration to the serosal surfaces. Neutrophil infiltration of the small vessels is a key histological feature of HSPN. Observation that blood and urinary leukotriene B₄ (LTB₄) levels are higher while lipoxin A₄ (LXA₄) levels are lower in patients with HSPN compared to patients without is consistent with this association [31]. Indeed, recruitment of neutrophils and chemotaxis are activated by LTB₄ and inhibited by LXA₄.

The clinical course of IgAN is variable. Studies from around the world have shown that about 10 % (3–25 %) of all patients with IgAN have complete resolution of hematuria and proteinuria (although regression of renal lesions and disappearance of mesangial deposits are rare). The most common clinical course is an indolently slow progression to renal insufficiency which occurs in 40–45 % of patients at 20 years of follow-up, half of whom reaching ESRD (i.e., 20–25 % of the total). The actuarial renal survival at 10 years of 4,153 patients recruited from 23 studies in Europe, Australia, Asia, and North America ranged from 77 % to 94 %, 87 % to 93 %, 74 % to 91 %, and 57 % to 67 %, respectively.

This variability is due to diverse diagnostic approaches since a strategy of early renal biopsy in patients with mild urine abnormalities and normal renal function will increase the proportion of IgAN patients with good prognosis. Performing renal biopsy at a late stage will select patients with advanced disease and poor prognosis.

Stable renal function is generally detected in subjects with mild forms of mesangial proliferation, while deterioration of renal function occurs in patients with advanced histological lesions. IgAN prognosis is also more favorable when observation begins at the time of the first symptoms rather than at the renal biopsy [45].

A multicenter study on IgAN collecting data from three continents showed that the overall 10-year renal survival rate was 77 % with a wide range from 93.3 % in Helsinki to 61.4 % in Toronto. Median slope creatinine clearance ranged between −1.24 ml/min/year in Helsinki and −3.99 ml/min/year in Toronto. Taking into account age, creatinine clearance, proteinuria, and mean arterial pressure, this study suggests that variability is mainly related to “lead-time bias” and to the inclusion of milder cases in centers with apparently good outcomes [46]. Further studies are needed to determine whether geographic differences may also be related to genetic factors, environmental factors, or differences in medical management.

Older age at diagnosis has an adverse influence on outcome, while episodes of macroscopic hematuria do not confer a worse prognosis.

A small proportion of patients present with macroscopic hematuria, acute nephritic syndrome, and rapid progression to ESRD over 2–3 years. The main histological features of these cases are crescents (often focal and segmental).

Arterial hypertension, severe proteinuria, impairment of renal function at presentation, as well as histological evidence of glomerular sclerosis and interstitial fibrosis have been reported as strong predictors of unfavorable outcome [45]. Hyperuricemia, increased body mass index, and hyperlipidemia are independent factors of progression [47].

Prognostic formulas that use simple clinical and laboratory data have also been proposed [48, 49].

Berthoux et al. calculated the absolute renal risk (ARR) of dialysis. ARR was obtained by counting a number of risk factors present at diagnosis: hypertension, proteinuria >1 g/day, and severe pathological lesions (overall optical score >8) [50]. The cumulative incidence of death or dialysis at 10 and 20 years in adequately treated patients was 2 % and 4 % for ARR = 0, 2 % and 9 % for ARR = 1, 7 % and 18 % for ARR = 2, and 29 % and 64 % for ARR = 3.

Achieving hypertension control and reducing proteinuria lowered the risk of death or dialysis [50].

ARR scoring at diagnosis proved to be useful in estimating at an early stage the final risk of dialysis/death of IgAN patients.

A more complex score using proportional hazard risk models has been proposed to determine the predictors of ESRD in IgAN [51]. In this study, systolic hypertension, proteinuria, hypoproteinemia, azotemia, and high histological grade at initial renal biopsy were independently associated with the risk of ESRD. Mild hematuria was found to predispose patients to ESRD more than severe hematuria. Using eight clinical and pathological variables, a scoring system was developed to estimate 7-year ESRD risk by ROC curve analysis. Patients were subdivided into five groups according to estimated risk (ER), minimum risk (ER = 0–0.9 %), low risk (ER = 1.0–4.9 %), moderate risk (ER = 5.0–19.9 %), high risk (ER = 20.0–49.9 %), and very high risk (ER = 50.0–100 %). The incidence of ESRD over 7 years was 0.2, 2.4, 12.2, 40.2, and 80.8 %, respectively [51].

HSPN is usually a self-limited condition that lasts an average of 4 weeks. A considerable minority of patients relapse. However, relapses usually subside after 6 months. Nephritis occurs in 40 % of patients (within 1 month from onset in 85 % of cases and in nearly all within 6 months). Persistent purpura, severe abdominal symptoms, and an older age are significant risk factors for later nephropathy. Nephritis is a unique feature with potentially chronic consequences that influences the long-term prognosis. It could be estimated that 2 % of all HSPN patients from unselected series will develop chronic kidney disease, but the risk of progression increases up to 20 % at 20 years in tertiary centers. In general, patients with microscopic hematuria and low-grade proteinuria have an excellent prognosis. By contrast, nephritic or nephrotic syndrome has a poor prognosis, with 20–40 % of patients developing long-term renal impairment. A poor correlation between histological features and ultimate outcome has been reported [29].

Glomerulosclerosis, tubular atrophy, and tubular fibrosis as well as mesangial and endocapillary proliferation and extensive crescents are histological predictors of bad prognosis. A number of classifications have been proposed to identify prognostic factors in IgAN [3, 87–89].

Recently, the Renal Pathology Society together with the International Group of IgAN Network supported an international consensus on the predictive role of the main histological lesions, the Oxford classification [90, 91]. Two hundred and sixty-five biopsies from patients with IgAN with proteinuria greater than 0.5 g/24 h and eGFR more than 30 ml/min/1.73 m² at the time of diagnosis who had been followed up for at least 1 year were included. Twenty histological lesions were identified, and six of particular relevance were selected on the basis of frequency and reproducibility: mesangial proliferation and endocapillary proliferation, crescents, segmental sclerosis and synechiae, tubular atrophy and interstitial fibrosis, and arterial score. Four of these variables, (1) the Mesangial hypercellularity score, (2) Segmental glomerulosclerosis, (3) Endocapillary hypercellularity, and (4) Tubular atrophy/interstitial fibrosis, were able to predicting renal outcome independent independently of clinical assessment (Table 8.2). Validation of the Oxford classification has been carried out in children as well as in adults [92–94]. Verification is necessary because premature implementation of biased conclusions can harm patients and mislead future research. In some studies mesangial hypercellularity and segmental glomerulosclerosis were weaker predictors than others [93, 94]. In a retrospective analysis of 187 adults and children with IgAN, the four individual variable of MEST offered the same predictive value in both cohorts except mesangial hypercellularity, which was a weaker predictor than in the original Oxford classification paper [94]. Bellur et al. compared the immunofluorescence pattern with optical findings categorized according to the Oxford classification score system and demonstrated the supportive role of IgG and the deposition of IgA in the capillary wall in predicting the development of proliferative glomerulopathy [95]. The Oxford classification has also been validated for in children with IgAN [93, 96]. Recently, Alamartine et al. carried out a validation in 183 adult patients who had IgAN and were followed for an average of 77 months. In univariate time-independent analyses T, E, and S lesions of MEST score were strongly associated with doubling creatinine or ESRD. Conversely, M lesion was not associated with renal outcome. In the multivariate model, only estimated GFR at baseline was a risk factor, and pathological lesions had no independent influence [97]. Proteinuria and blood pressure also failed to predict survival independently from a combined event when factoring in the initial eGFR.

Validation studies include categories of patients that are similar but not identical to the original study so that duplicating every result is not expected [98]. Despite the rigor of the methodology adopted, the Oxford classification remains the result of a retrospective observation, and although special attention was paid to search for independent risk factors, confounding factors cannot be ruled out. Prospective studies are therefore needed to further evaluate these results. For instance, since cases who had been followed up for less than 1 year have been not examined, a number of patients with rapidly progressive IgAN or advanced CKD have been excluded. Conversely, excluding patients with proteinuria <0.5 g/24 h means excluding cases with more favorable prognosis. The involvement of patients from eight different countries made the cohort more varied and representative, though it was not possible to guarantee the homogeneity of the laboratory findings. Analyzing renal survival using two different statistical methods of multivariate analysis provided different results for segmental glomerulosclerosis and for mesangial hypercellularity. The histological study was carried out with PAS staining alone, which, by itself, is not ideal for all the lesions observed in the first stage of the study. Besides, no immunofluorescence or electron microscopy correlations have been investigated. These issues could be the aims of further refinement of the classification.

As previously discussed, IgAN is characterized by a variable clinical profile (ranging from a benign course to rapidly progressive renal failure) and a wide spectrum of histological lesions.

Up to 23 % of patients, i.e., those who do not develop proteinuria >300 mg/24 h or hypertension during the follow-up, will have complete clinical remission [99]. Patients whose urinary protein excretion increases during the follow-up are more likely to develop renal impairment compared to patients without proteinuria [99].

Proteinuria is the most important predictor of the decline of GFR rate in studies using multivariate analysis [100]. Five patterns of progression have been identified on the degree of proteinuria: <0.3 g/day, 0.3–1 g/day, 1–2 g/day, 2–3 g/day, and >3 g/day. The kidney survival curve at 15 years was 96 %, 87 %, 65 %, 55 %, and 30 %, respectively. Nevertheless, patients presenting with baseline proteinuria >3 g/day who achieved partial remission, especially if proteinuria dropped to levels less than 1 g/day, had a course similar to patients presenting with <1 g/day at diagnosis [100]. A treatment goal of <0.5 g/day per 1.73 m² is recommended in children [101]. Values of proteinuria equal or less than 0.5 g/day [102] have been reported as a threshold of risk in adults as well.

Uncontrolled hypertension is associated with greater proteinuria and faster decline of GFR [89, 103], while reducing blood pressure has protective effects especially in mild renal insufficiency [103]. In order to achieve maximal renal and cardiovascular protection, blood pressure goals <130/80 mmHg in patients with less than 300 mg/24 h of proteinuria, and <125/75 in patients with proteinuria >1 g/24 h are recommended [104–106].

Low GFR at presentation was also listed among the clinical factors of poor prognosis [45], but this issue remains controversial [89, 107].

KDIGO guidelines recommend the assessment of all patients with biopsy-proven IgAN for secondary causes of disease, emphases on the role of pathological findings in assessing prognosis, and the evaluation of the risk factors of progression (i.e., proteinuria, blood pressure, and eGFR) at the time of diagnosis and during the follow-up [108–113].