IgA nephropathy: Clinical features and diagnosis

INTRODUCTION — IgA nephropathy (IgAN) is the most common cause of primary (idiopathic) glomerulonephritis in resource-abundant settings.

The epidemiology, pathology, clinical features, and diagnosis of IgAN will be reviewed here. Other aspects of IgAN are discussed separately:

●(See "IgA nephropathy: Pathogenesis".)

●(See "IgA nephropathy: Treatment and prognosis".)

●(See "IgA nephropathy: Recurrence after transplantation".)

●(See "IgA vasculitis (Henoch-Schönlein purpura): Kidney manifestations".)

EPIDEMIOLOGY — IgAN is the most common lesion found to cause primary glomerulonephritis throughout most resource-abundant countries of the world [1]. IgAN occurs with greatest frequency in East Asian individuals and White individuals and is relatively rare in Black individuals [2-4]. In a Chinese study of 13,519 kidney biopsies, for example, IgAN constituted 45 percent of all cases of primary glomerulonephritis [3]. An international kidney biopsy survey found that IgAN accounted for 22 and 11 percent of glomerular disease diagnoses in Europe and North America, respectively [5].

Variations in disease prevalence may reflect regional differences in screening for kidney disease and kidney biopsy practices [3,6]. IgAN can only be diagnosed upon evaluation of a kidney biopsy with immunofluorescence microscopy. Thus, the incidence and prevalence of IgAN will be higher in places where kidney biopsies are performed more frequently. Many patients with IgAN are detected on routine urine screening because their only clinical manifestation is asymptomatic hematuria and/or proteinuria. Prevalence may therefore appear to be higher in countries with an active urine testing program and a low threshold for the performance of kidney biopsy in patients with isolated asymptomatic hematuria, such as Japan and Korea, where testing is routinely performed in schools and in the workplace. Conversely, clinicians in North America seldom biopsy a patient with isolated hematuria or mild proteinuria, resulting in an apparently lower disease prevalence. In some resource-limited countries, the lack of routine immunofluorescence microscopy precludes an exact evaluation of disease prevalence.

Patients with IgAN may present at any age, but there is a peak incidence in the second and third decades of life. There is approximately a 2:1 male-to-female predominance in North American and Western European populations in both adults and children, although the sexes are equally affected among populations in East Asia [7,8]. Significant heterogeneity in clinical presentation and pathological features also exists between geographical locations, which may in part explain differences in response to immunomodulatory therapies [7].

PATHOLOGY

Histologic features — The pathognomic finding for IgAN is the presence of mesangial deposits of IgA, which are demonstrated by immunofluorescence microscopy.

●Immunofluorescence microscopy

•IgA – Immunofluorescence microscopy demonstrates dominant or codominant mesangial deposits of IgA, either alone, with IgG, with IgM, or with both IgG and IgM (picture 1 and picture 2) [1]. Deposited IgA is predominantly J chain-containing polymeric IgA1, with a predominance for lambda light chains. Subendothelial capillary wall IgA deposits may also be present in up to one-third of patients, and this is associated with higher histologic activity (increased mesangial and endocapillary hypercellularity) and worse kidney outcome [9]. IgG codeposition is observed in approximately one-third of cases and has been reported to be an independent risk factor for poor kidney outcome [10]. Mesangial deposition of secretory IgA has also been observed, although the pathogenic significance of this is unknown [9-11].

The immunofluorescence findings in IgAN are indistinguishable from those in IgA vasculitis (Henoch-Schönlein purpura) nephritis. (See "IgA vasculitis (Henoch-Schönlein purpura): Kidney manifestations".)

•Complement – Glomerular deposition of complement component C3 is found in over 90 percent of cases [12]. C1q is almost always absent, implying that complement is activated via the alternative and/or lectin pathways. Deposits of components of the alternative pathway, properdin and Factor H, may often be found [12]. Glomerular deposition of complement factor H-related protein 5 (CFHR5), a positive regulator of the alternative pathway, was observed more frequently in patients with progressive IgAN compared with those who have nonprogressive disease [13]. The presence of mesangial C4d deposits, signifying lectin pathway activation in the absence of C1q, has been identified as a risk factor for worse long-term kidney outcomes in IgAN [13-16].

•Other – Glomerular fibrin deposition may be observed in the mesangium or along the endothelial surface, although this is more commonly seen in IgA vasculitis (Henoch-Schönlein purpura) nephritis. (See "IgA vasculitis (Henoch-Schönlein purpura): Kidney manifestations".)

●Light microscopy – While mesangial IgA deposition is diffuse and global in IgAN, there is significant heterogeneity in the pathologic response to this deposition, which may be focal (involving less than 50 percent of glomeruli) and segmental. The major finding on light microscopy, mesangial hypercellularity and matrix expansion, is commonly focal (picture 3) [17]. In patients with IgAN and rapidly deteriorating kidney function, segmental necrosis with or without crescent formation is often seen, a finding consistent with an ongoing "capillaritis."

A later diagnosis with decreased glomerular filtration rate (GFR) and increased proteinuria is commonly associated with a kidney biopsy displaying features of chronic disease: glomerulosclerosis, tubulointerstitial inflammation, tubular atrophy, and interstitial fibrosis [18].

Thrombotic microangiopathy (TMA) has been variably described in association with IgAN. It is often associated with uncontrolled or malignant hypertension and portends a poor kidney outcome [19-22]. This lesion was not commonly observed in the Oxford classification study and subsequent validation studies and, therefore, may be subject to variability in its interpretation [23]. (See 'Oxford classification of IgAN' below.)

●Electron microscopy – Electron microscopy typically reveals electron-dense deposits that are primarily limited to the mesangium (which are outside of mesangial cells in the mesangial spaces) but may also occur in the subendothelial and subepithelial spaces. The number and size of these deposits generally correlates well with the severity of changes seen on light microscopy [17].

Some patients with IgAN have coexisting diffuse thinning of the glomerular basement membrane that is indistinguishable from thin basement membrane nephropathy [24,25]. Exome sequence analysis of patients with IgAN and thin basement membrane disease has identified diagnostic variants of the COL4A3/COL4A4/COL4A5 genes in one-third of cases [26]. It is not clear whether the clinical course of such patients differs from typical IgAN [24,25]. Observational data from France suggests that such patients may have a more benign outcome, due possibly to lead-time bias, as hematuria brings them to the attention of clinicians at an earlier time in the natural history of disease [27]. (See "Thin basement membrane nephropathy (benign familial hematuria)".)

There is some evidence that a subset of IgAN cases with clinical features resembling those of minimal change disease display biopsy features typical of a podocytopathy. Whether this represents a discrete subclass of IgAN remains to be clarified [28].

Oxford classification of IgAN — In 2009, a pathologic classification of IgAN was developed by the International IgA Nephropathy Network in collaboration with the Renal Pathology Society, based upon clinical data and kidney biopsies from 265 White patients and East Asian patients followed for a median of five years [29,30]. This pathologic scoring system, known as the Oxford classification, scores kidney biopsies based upon histologic variables that have been shown to independently predict kidney outcome in patients with IgAN. The Oxford classification schema has subsequently been validated in several cohorts and refined for clinical use in both adults and children with IgAN [31-35].

Based upon this work, the consensus recommendation is that every biopsy report of IgAN should include numerical scores based upon the presence or absence of the following five variables (MEST-C) [36]:

●Mesangial hypercellularity – Mesangial cells are counted per mesangial area, and a score of zero to three is assigned for each glomerulus. A score of zero indicates that fewer than four mesangial cells are present per mesangial area; a score of one indicates that four to five mesangial cells are present per mesangial area; a score of two indicates that six to seven mesangial cells are present per mesangial area; a score of three indicates that greater than eight 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.

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

●Segmental glomerulosclerosis – This is defined as present (S1) if any part of the glomerular tuft is involved in sclerosis, or absent (S0) if no segmental glomerulosclerosis is present.

●Tubular atrophy/interstitial fibrosis – 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 to 25, 26 to 50, or >50 percent, respectively. Note that scoring of tubular atrophy/interstitial fibrosis was preferred to global glomerulosclerosis, as its quantification is less susceptible to error due to subcapsular sampling or paucity of glomeruli on the biopsy.

●Crescents – This feature is defined as present if cellular and/or fibrocellular crescents are present in at least one glomerulus (C1), present in at least 25 percent of glomeruli (C2), or absent (C0). Fibrous crescents are not counted toward this score.

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

A number of pathological features occasionally found in IgAN were not included on the Oxford classification, such as interstitial inflammation, TMA, and fibrinoid necrosis. This may be due to lack of interobserver reliability or that these lesions were not commonly observed, which may in part be due to patient selection (patients with rapidly progressive disease were excluded from the original cohort).

A prediction tool, which combines clinical and histologic (MEST-C) data at diagnosis, has been developed and externally validated and predicts the risk of worsening kidney function (defined by a 50 percent decline in eGFR or development of ESKD) within five years from kidney biopsy [37]. Use of this prediction tool is discussed in more detail elsewhere. (See "IgA nephropathy: Treatment and prognosis", section on 'Assessment of risk'.)

IgA deposits in healthy individuals — IgA deposits may be seen on kidney biopsies of individuals with no evidence of kidney disease [38]. The reported incidence of mesangial IgA deposition in apparently healthy individuals ranges from 3 to 16 percent [38-40]. These cases had no clinical features of nephritis, but their kidney biopsy was consistent with IgAN.

This observation raises three important points:

●There is a large cohort of undiagnosed "latent" IgAN in the general population, most pronounced in East Asian populations.

●This finding must be considered when genetic studies are undertaken comparing gene polymorphisms in IgAN with "healthy" populations.

●It raises an important consideration for the pathogenesis of IgAN: The process of mesangial IgA deposition may be separate from the induction of glomerular injury, and IgA deposition does not necessarily need to be followed by nephritis. Identifying the independent factors that may be critical to each of these processes may improve our overall understanding of the pathogenesis of IgAN. (See "IgA nephropathy: Pathogenesis".)

Interestingly, there have been cases reported of patients who have inadvertently received a kidney transplant containing IgA deposits. These deposits have been shown to resolve on subsequent biopsy of the graft, indicating that the disease process in IgAN is systemic rather than being confined to the kidney [40,41].

CLINICAL FEATURES

Clinical presentations — Patients with IgAN may present with a range of clinical presentations, from asymptomatic microscopic hematuria to rapidly progressive glomerulonephritis. The relative frequency of these presentations depends in part upon screening practices (which will lead to increased discovery of asymptomatic cases) and the particular population being evaluated [2,6]. As an example, some studies have shown that patients of South or East Asian ancestry with IgAN, compared with those of other origin, may present with more severe clinical features and have a higher risk of progression to ESKD [42-44].

Clinical presentations among patients with IgAN including the following:

●Gross hematuria – Approximately 40 to 50 percent present with one or recurrent episodes of gross (visible) hematuria, often accompanying an upper respiratory infection. This has sometimes been called "synpharyngitic hematuria." These episodes can be provoked by bacterial tonsillitis or by viral upper respiratory infections; they may also occur rarely in individuals who have already undergone tonsillectomy. It is frequently presumed, although not proven, that the first episode represents the onset of the disease. Patients may complain of flank pain during acute episodes, which usually reflects stretching of the kidney capsules. Low-grade fever may also be present. These features can mimic urinary tract infection or urolithiasis. Most patients have only a few episodes of gross hematuria, and episodes usually recur for a few years at most. An initial episode of gross hematuria at age 40 years or older is rarely due to IgAN, and other diagnoses must be assessed. (See "Etiology and evaluation of hematuria in adults" and "Glomerular disease: Evaluation and differential diagnosis in adults".)

●Microscopic hematuria with or without proteinuria – Another 30 to 40 percent have microscopic hematuria and usually mild proteinuria and are incidentally detected on a routine examination or during a diagnostic evaluation for chronic kidney disease [45,46]. In these patients, the disease is of uncertain duration. On urine microscopy, dysmorphic red blood cells, and in particular urinary acanthocytes, are regarded as being an indicator of glomerular pathology [47]. Gross hematuria will eventually occur in 20 to 25 percent of these patients. (See "Glomerular disease: Evaluation and differential diagnosis in adults", section on 'Isolated glomerular hematuria'.)

●Nephrotic syndrome or rapidly progressive glomerulonephritis – Less than 10 percent present with either nephrotic syndrome or an acute, rapidly progressive glomerulonephritis characterized by edema, hypertension, and kidney function impairment as well as hematuria. Rarely, IgAN may present with malignant hypertension. It is usually presumed that patients have longstanding disease that was not detected earlier because the patient did not have gross hematuria or undergo routine urinalysis.

●Acute kidney injury – Rarely, patients develop acute kidney injury with or without oliguria. This may be due to crescentic IgAN or to heavy glomerular hematuria leading to tubular occlusion and/or damage by red cells. The latter is usually a reversible phenomenon, although incomplete recovery of kidney function may occur [48]. If there is crescentic IgAN, there will be an increase in the absolute number of dysmorphic red cells excreted in the urine that is typically at least 50 percent of all red cells seen.

Differences between children and adults — In children with IgAN, gross hematuria is more common than in adults, which may lead to earlier diagnosis [8,49]. Inflammatory lesions and mesangial and/or endocapillary hypercellularity are also more prevalent on kidney biopsy in children with IgAN compared with adults [31]. In contrast with adults, who usually have a linear rate of estimated glomerular filtration rate (eGFR) decline, children experience an initial increase in eGFR, which may last up to several years, followed by a linear decline similar to that seen in adults [50]. Postulated causes for this include the more frequent episodes of acute nephritic syndrome and hematuria and higher rates of clinical remission in children compared with adults.

Associated conditions — IgAN may be associated with other conditions [51]. Some associations are well established, others are anecdotal observations that should be interpreted with caution because IgAN is a common disease, and any association may be coincidental rather than causal. As previously mentioned, the reported incidence of mesangial IgA deposition in apparently healthy individuals ranges from 3 to 16 percent [38,39]. Thus, the likelihood of finding mesangial IgA deposits by chance in association with other common diseases is relatively high. (See 'IgA deposits in healthy individuals' above.)

●Chronic liver disease – Mesangial IgA deposition associated with chronic liver disease, particularly alcoholic cirrhosis, is the most common form of secondary IgAN [52,53]. It can also occur in chronic liver disease due to other causes, including hepatitis B and C [54,55] and, in children, end-stage liver disease due mostly to alpha-1 antitrypsin deficiency or biliary atresia [56]. Despite the frequency of glomerular IgA deposits in advanced liver disease, most adults have no clinical signs of glomerular disease [52-54], while up to one-third of children may have asymptomatic microscopic hematuria or proteinuria [56]. The urinary abnormalities that may be seen in children typically resolve after successful liver transplantation [56].

Impaired removal of IgA-containing complexes by the Kupffer cells in the liver is thought to predispose to IgA deposition in the kidney [57]. The observation that IgA may also be deposited in the skin and hepatic sinusoids is compatible with this hypothesis [58]. As in primary IgAN, polymeric IgA1 appears to be the dominant IgA isoform deposited, although there is some evidence for codeposition of IgA2.

●Celiac disease – Glomerular IgA deposition is common in celiac disease, occurring in as many as one-third of patients. As in liver disease, the great majority of affected patients have no clinical manifestations of kidney disease, perhaps because there is no associated activation of complement [59]. (See "Epidemiology, pathogenesis, and clinical manifestations of celiac disease in adults".)

Ingestion of gliadin in this disorder leads to the formation of IgA antigliadin antibodies, with the subsequent deposition of gliadin-antigliadin immune complexes in the glomeruli [60]. This can occur in patients both with overt celiac disease and those with no symptoms but mucosal atrophy on intestinal biopsy. The level of circulating IgA complexes appears to correlate with disease activity in the occasional patient with clinically evident IgAN. However, gliadin deposition cannot be demonstrated in the glomeruli, suggesting that gluten might act by increasing intestinal permeability and enhancing the absorption of other dietary antigens [61].

Institution of a gluten-free diet in patients with circulating antigliadin antibodies results, in most cases, in a temporary but nonsustained reduction in microscopic hematuria and proteinuria and has no impact on long-term kidney survival [61,62].

●HIV infection – Although the collapsing variant of focal segmental glomerulosclerosis (FSGS) is the classic glomerulopathy seen with HIV infection, other glomerular diseases have also been associated with HIV infection, including IgAN [63-65]. Patients with IgAN present with gross or microscopic hematuria and asymptomatic proteinuria compared with the nephrotic syndrome in FSGS. (See "Overview of kidney disease in patients with HIV".)

The polyclonal increase in serum IgA, seen in HIV infection, has been cited as a predisposing factor. In at least some cases of HIV-associated IgAN, idiotypic IgA antibodies reactive with anti-HIV IgG or IgM antibodies can be demonstrated both in the systemic circulation and in the kidney [65]. Furthermore, the HIV genome can be detected in the kidney, suggesting a possible initiating role of viral infection in the glomerular cells.

The prevalence of IgA deposits in patients infected with HIV is uncertain. One report of 116 postmortem examinations found mesangial IgA deposits in 8 percent of patients [63]. However, most affected patients had little or no mesangial hypercellularity, and urinary abnormalities were mild in all cases. Thus, subclinical disease or incidental IgA deposition appears to be much more common than overt IgAN, similar to the findings noted above in cirrhosis and celiac disease.

●Monoclonal gammopathy of renal significance (MGRS) – These are a group of disorders in which a monoclonal protein causes kidney damage but without evidence of overt hematological malignancy (see "Diagnosis and treatment of monoclonal gammopathy of renal significance"). In MGRS, deposition of monoclonal IgA occurs less frequently compared with IgG. Two subtypes of glomerulopathies have been described: alpha-heavy chain deposition disease and IgA-proliferative glomerulonephritis with monoclonal immunoglobulin deposits (IgA-PGNMID), which shares common clinical and pathological features with IgG-PGNMID [66]. Distinction between these conditions and IgAN, where polyclonal IgA is deposited, is important as IgA-associated MGRS may respond to clone-directed therapies.

●Glomerular diseases – IgAN may occur in association with other glomerular disorders:

•Minimal change disease – Some patients with IgAN have an acute onset of the nephrotic syndrome in which there is only mild mesangial proliferation on kidney biopsy and the most prominent finding is diffuse foot process effacement, similar to that seen in minimal change disease [67-70]. This presentation is more frequent in children [71]. Many of these patients behave as if they have minimal change disease, with remission of proteinuria being induced by glucocorticoid therapy. The mechanism underlying this association is not understood, and the IgA deposits may represent a chance occurrence [68]. (See "IgA nephropathy: Treatment and prognosis", section on 'IgA nephropathy with apparent minimal change disease'.)

•Granulomatosis with polyangiitis – IgAN has been described in patients with granulomatosis with polyangiitis who were in clinical remission after initial immunosuppressive therapy [72]. These patients had repeated upper respiratory infections (perhaps due in part to the immunosuppression) and presented with new hematuria, but no apparent recurrence of systemic vasculitis or new elevation in anti-neutrophil cytoplasmic antibodies titers. The latter findings suggest the possibility of a new kidney disease rather than relapsing vasculitis. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Clinical manifestations and diagnosis".)

There are also a number of reports documenting IgA deposition in patients with thin basement membrane nephropathy, lupus nephritis, diabetic nephropathy, membranous nephropathy, and IgA-dominant Staphylococcus-associated postinfectious glomerulonephritis. With the exception of IgA-dominant postinfectious Staphylococcus-associated glomerulonephritis, these findings are most probably due to chance associations because IgA deposition is common in the general population. (See "Staphylococcus-associated glomerulonephritis in adults".)

●Other conditions – IgAN has been infrequently associated with a variety of other diseases including dermatitis herpetiformis, seronegative arthritis (particularly ankylosing spondylitis), small cell carcinoma, lymphoma (Hodgkin lymphoma and T-cell lymphomas, including mycosis fungoides), disseminated tuberculosis, bronchiolitis obliterans, and inflammatory bowel disease (Crohn disease and ulcerative colitis) [73-84].

DIAGNOSIS

When to suspect IgAN — Given the range of clinical presentations among patients with IgAN (see 'Clinical presentations' above), the diagnosis of IgAN should be suspected in any patient who presents with one or more of the following clinical features:

●One or more episodes of gross hematuria, especially if accompanied by an upper respiratory infection

●Persistent microscopic hematuria with or without proteinuria

●Slowly progressive kidney function impairment

As discussed previously, patients with IgAN may present less commonly with nephrotic syndrome or rapidly progressive glomerulonephritis.

Establishing the diagnosis — The diagnosis of IgAN is confirmed by kidney biopsy, with immunofluorescence or immunoperoxidase staining demonstrating the presence of dominant or codominant deposition of IgA. There are no specific laboratory findings that can be used to reliably diagnose IgAN. After a diagnosis of IgAN has been established, underlying causes of secondary IgAN (eg, liver cirrhosis) should be considered according to the patient's coexisting medical conditions. (See 'Histologic features' above and 'Associated conditions' above.)

However, a kidney biopsy may not be indicated in every patient suspected of having IgAN, depending upon their clinical presentation. As an example, a kidney biopsy is not usually performed for patients presenting with isolated hematuria (ie, without evidence of proteinuria or impaired kidney function), since establishing the diagnosis frequently does not alter the course of treatment in such patients. In such patients, a kidney biopsy is usually performed only if there are signs suggestive of more severe or progressive disease, such as persistent proteinuria of at least 500 mg per day or an elevated serum creatinine concentration. Indications for performing a kidney biopsy vary geographically, and in some countries, there is a greater willingness of nephrologists to biopsy patients who have persistent microscopic hematuria with preserved kidney function and without proteinuria. (See "The kidney biopsy", section on 'Appropriate use of kidney biopsy' and "Etiology and evaluation of hematuria in adults", section on 'Role of kidney biopsy'.)

This geographic variability in kidney biopsy indications may, at least in part, explain why IgAN is diagnosed at earlier stages of disease in some countries and at later stages in others. In a study from Japan, for example, where mandatory kidney screening programs have been implemented since the 1970s, approximately 30 percent of patients with biopsy-proven primary IgAN had chronic kidney disease (CKD) stage 3 or higher, and approximately 5 percent had CKD stage 4 or 5 at the time of diagnosis [85]. By contrast, in a study from the United States (which does not have mandatory kidney screening programs), 75 percent of patients had CKD stage 3 or higher, and 42 percent had CKD stage 4 or 5 at the time of diagnosis [86]. Higher CKD stages were associated with an increased odds of higher Oxford classification (MEST-C) scores (more extensive histological injury). Thus, deferring a kidney biopsy until the patient has evidence of more severe disease may result in patients being diagnosed at later stages in the disease course. (See 'Oxford classification of IgAN' above.)

A number of other tests have been proposed for the evaluation and diagnosis of IgAN, including measurement of poorly galactosylated IgA1 O-glycoforms and/or poorly galactosylated IgA1-specific IgG antibodies in the serum [87,88], and measurement of certain microRNAs (miRNAs) that affect O-galactosylation of IgA1 [89,90], among others. However, none of these tests have clearly been shown to have utility as diagnostic biomarkers for IgAN.

DIFFERENTIAL DIAGNOSIS — In patients who are suspected of having IgAN, the differential diagnosis includes the following conditions:

●Alport syndrome (also referred to as hereditary nephritis) and thin basement membrane nephropathy are the two other major glomerulopathies that present with persistent isolated hematuria [91,92]. The diagnosis of any of these disorders can only be made by kidney biopsy, or by inference in Alport syndrome if there is a family history of kidney failure with or without deafness, or in thin basement membrane disease if approximately one-half of first-degree relatives have hematuria. (See "Isolated and persistent glomerular hematuria in adults", section on 'Causes'.)

●Poststreptococcal glomerulonephritis (PSGN) may also present with gross hematuria after an upper respiratory tract infection. However, the time interval between the antecedent illness and the development of hematuria is usually longer in PSGN (more than 10 versus less than 5 days in IgAN). In addition, patients with IgAN may have repeated episodes of gross hematuria, which are rare in PSGN. (See "Poststreptococcal glomerulonephritis", section on 'Clinical manifestations'.)

●Immune complex/monoclonal immunoglobulin- or complement-mediated membranoproliferative glomerulonephritis may also present with episodic gross hematuria in children and young adults and should therefore be considered in the differential diagnosis. (See "Membranoproliferative glomerulonephritis: Classification, clinical features, and diagnosis".)

●IgA-dominant Staphylococcus-associated glomerulonephritis typically presents with acute kidney injury, hematuria, and proteinuria. Older adult patients and those with diabetes mellitus are most commonly affected. The majority of reported cases are associated with Staphylococcus aureus infection [93]. In contrast with poststreptococcal glomerulonephritis, in which glomerular deposition of IgG and/or C3 is predominant, IgA-dominant Staphylococcus-associated glomerulonephritis is characterized by IgA deposition [94]. Diffuse proliferative glomerulonephritis with infiltration of neutrophils and subepithelial and subendothelial electron-dense deposits are more prevalent in Staphylococcus-associated glomerulonephritis. (See "Staphylococcus-associated glomerulonephritis in adults", section on 'Distinction from IgA nephropathy'.)

●IgA vasculitis (Henoch-Schönlein purpura) has kidney findings that are histologically identical to that in IgAN. However, patients with IgA vasculitis typically have other extrarenal manifestations, such as rash, arthralgias, and abdominal pain. (See "IgA vasculitis (Henoch-Schönlein purpura): Kidney manifestations".)

●Lupus nephritis is another disorder associated with prominent mesangial IgA deposition. Lupus nephritis can be distinguished from IgAN histologically by the more prominent deposition of IgG than IgA and the presence of substantial C1q deposition, indicating activation of the classical complement pathway, as opposed to activation of the alternative and/or lectin pathway in IgA nephropathy [2]. (See "Lupus nephritis: Diagnosis and classification".)

●Other differential diagnoses include Fabry disease (which has been reported to occur coincidentally with IgAN [95]), non-IgA mesangial proliferative glomerulonephritis, and MGRS including IgA-PGNMID. (See 'Associated conditions' above.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Glomerular disease in adults".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: IgA nephropathy (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Epidemiology – IgA nephropathy (IgAN) is the most common lesion found to cause primary glomerulonephritis throughout most resource-abundant countries of the world. Patients with IgAN may present at any age, but there is a peak incidence in the second and third decades of life. There is a 2:1 male-to-female predominance in North American and Western European populations in both adults and children, although the sexes are equally affected among populations in East Asia. (See 'Epidemiology' above.)

●Pathology – IgAN is characterized pathologically by prominent, globular deposits of IgA in the mesangium on immunofluorescence microscopy. Light microscopy shows diffuse mesangial proliferation and matrix expansion with proliferative glomerulonephritis and segmental glomerulosclerosis and tubulointerstitial fibrosis and inflammation in more advanced disease. Electron microscopy shows dense deposits primarily in the mesangium (picture 1 and picture 3 and picture 2). The Oxford classification of IgAN identifies variables that are correlated with kidney outcomes independent of the clinical features at baseline, the proteinuria level, and blood pressure control. (See 'Pathology' above.)

●Clinical features – Most patients with IgAN present with either gross hematuria (single or recurrent), usually accompanying an upper respiratory infection, or microscopic hematuria with or without mild proteinuria incidentally detected on a routine examination. These symptoms are often accompanied by hypertension. Less commonly, patients may present with either nephrotic syndrome or an acute, rapidly progressive glomerulonephritis. Patients may rarely develop acute kidney injury with or without oliguria, due to crescentic IgAN or to gross hematuria causing tubular occlusion and/or damage by red cells. (See 'Clinical features' above.)

●Associated conditions – IgAN may be associated with other conditions. Mesangial IgA deposition, which is often clinically silent, may also be seen with chronic liver disease, celiac disease, HIV infection, and monoclonal gammopathy of renal significance (MGRS). In addition, IgAN may rarely be seen with other glomerular diseases, including minimal change disease, membranous nephropathy, and granulomatosis with polyangiitis. (See 'Associated conditions' above.)

●Diagnosis – The diagnosis of IgAN should be suspected in any patient who presents with one or more episodes of gross hematuria (especially if accompanied by an upper respiratory infection), persistent microscopic hematuria with or without proteinuria, or slowly progressive kidney function impairment. The diagnosis is confirmed by kidney biopsy. However, a kidney biopsy is usually performed only if there are signs suggestive of more severe or progressive disease, such as persistent proteinuria of at least 500 mg per day or an elevated serum creatinine concentration. (See 'Diagnosis' above.)

ACKNOWLEDGMENT — The editorial staff at UpToDate acknowledges John Feehally, DM, FRCP, who contributed to an earlier version of this topic review.