bubble_chart Overview

Non-IgA mesangial proliferative glomerulonephritis (non-IgA mesangial proliferative glomerulonephritis) refers to a group of diseases characterized by diffuse mesangial cell proliferation and/or widening of the mesangial matrix under light microscopy. The reported incidence of this group of diseases varies significantly across regions. For example, in the United States, these diseases account for less than 10% of primary nephrotic syndrome cases, whereas in China, they are quite common, accounting for about 30%. If calculated based on the number of renal biopsies for primary glomerular diseases, the proportion can be as high as 40%. These differences are related not only to geographic, ethnic, and environmental factors but also to specimen preparation, the disease stage at the time of biopsy, and evaluation criteria.

Since mesangial proliferative glomerulonephritis is merely a pathological descriptive concept, it encompasses various conditions. Among primary glomerular diseases, there is significant overlap between mesangial proliferative glomerulonephritis, minimal change nephropathy, and focal segmental glomerulosclerosis. Minimal change nephropathy can also exhibit some degree of mesangial proliferation, while mesangial proliferative glomerulonephritis may show focal segmental exacerbation or even focal segmental sclerosis. Additionally, repeated renal biopsy findings can transition between these conditions, and responses to treatment are inconsistent. Thus, some suggest that these three histological types may represent different severity levels of the same disease. Whether mesangial proliferative glomerulonephritis is an independent disease and its relationship with minimal change nephropathy and focal segmental glomerulosclerosis remain to be further elucidated.

Under light microscopy, this group of diseases is often indistinguishable from the resolution phase of acute post-streptococcal glomerulonephritis (diffuse endocapillary proliferative glomerulonephritis) and the early stage of mesangiocapillary proliferative glomerulonephritis (before mesangial tissue invades the subendothelial space).

In immunofluorescence studies, the types and intensity of immunofluorescence-positive deposits vary widely: those predominantly IgA-positive are classified as IgA nephropathy; those predominantly IgM and/or C₃ mesangial deposits are sometimes referred to as "IgM nephropathy," though this term is not widely accepted; those with predominant Ig and/or C₃ deposits also exhibit various patterns; and some show no immunofluorescence-positive deposits. Secondary glomerular diseases with similar morphological presentations are even more numerous, such as systemic lupus erythematosus, Henoch-Schönlein purpura, rheumatoid arthritis, hereditary nephritis, Goodpasture syndrome, Kimura disease, and renal damage caused by D-penicillamine. Renal damage from vasculitis is also similar but often accompanied by necrotizing changes in the glomerular tufts. This section focuses on primary mesangial proliferative glomerulonephritis and excludes the aforementioned other diseases.

bubble_chart Pathogenesis

The disease often has an insidious onset, with some cases preceded by a history of infection, most commonly upper respiratory infections, though the specific pathogen remains unidentified. The exact role of infection in the disease is still unclear. The pathogenesis of membranoproliferative glomerulonephritis is unknown, but immunofluorescence studies suggest it is an immune complex disease. The nature of the antigens and antibodies involved remains uncertain. Although poorly soluble and insoluble immune complexes are significant contributors to membranous damage, the precise mechanisms are not fully understood. The degree of membranous proliferation can be influenced by various factors such as the size, quantity, charge, and shape of the immune complexes. When membranous function is impaired or suppressed, immune complexes or macromolecular substances that cannot be processed or transported may accumulate in the membranous region, potentially leading to membranous lesions.

bubble_chart Pathological Changes

Under light microscopy, diffuse mesangial cell proliferation can be observed, with 4 to 5 cells per mesangial area, and in severe cases, exceeding 5; endothelial cells may also proliferate, usually mildly; infiltrating monocytes may be present among the proliferating cells; mesangial matrix increases; although segmental exacerbation may sometimes occur, the presentation is typically diffuse and uniform; the glomerular capillary walls remain intact, with no evidence of tuft necrosis; adhesion and sclerotic changes are usually absent. Approximately half of the patients exhibit eosinophilic deposits within the glomeruli, confined to the mesangial area. Occasionally, similar eosinophilic deposits and "hyaline changes" may be observed in the glomerular capsule basement membrane and small stirred pulse walls. Mesangial cells and matrix do not extend into the peripheral capillary walls. Findings during immunofluorescence examination are highly variable. Cases dominated by IgA are classified as IgA nephropathy and are not discussed in this section. Common presentations include granular diffuse distribution dominated by IgG or IgM, possibly accompanied by mesangial C₃ deposits, as well as varying degrees of minor IgM, IgG, and IgA deposits. The disease mechanism and clinical significance of IgM-dominant deposits remain unclear. Some mesangial proliferative glomerulonephritis cases may lack immunoglobulin and complement deposits, raising debate over whether they should be classified as minimal change nephropathy with prominent mesangial proliferation. Rarely, only C₃ deposits may be present without immunoglobulin deposits. Electron microscopy typically reveals fine granular or homogeneous electron-dense deposits in the mesangial area. Some suggest that cases with large granular electron-dense deposits should exclude IgA nephropathy and systemic disease-related renal damage. Additionally, epithelial cells may exhibit foot process effacement and disappearance, and the basement membrane may show minor alterations.

bubble_chart Clinical Manifestations

Membranoproliferative glomerulonephritis can occur at any age but is more common in adolescents. Males are slightly more affected than females. About 30–40% of patients have a history of infection before onset, mostly upper respiratory tract infections. The onset is often insidious, with 20–25% presenting as acute nephritic syndrome, about 25% (up to 37% in children) as nephrotic syndrome, and the rest typically manifesting as asymptomatic proteinuria and/or hematuria. The incidence of hematuria is approximately 80%, which may present as recurrent episodes, gross hematuria, or microscopic hematuria. Proteinuria varies in severity but is usually non-selective. Around 30% of patients already have hypertension at diagnosis, though it is often grade I elevation. Renal pain may occur, either unilaterally or bilaterally, but this is uncommon. Most patients show normal renal function tests at diagnosis, with only a few exhibiting grade I impairment. Blood moistening and tonifying components are generally normal, and blood immunoglobulin levels rarely show significant abnormalities. Anti-streptolysin O titers are usually normal.

bubble_chart Treatment Measures

When renal biopsy in patients shows mild mesangial proliferation without immunoglobulin deposition or superimposed focal segmental glomerulosclerosis, the prognosis is often benign. Most of these patients respond well to glucocorticoids, although the treatment course needs to be appropriately prolonged. For those who do not respond, achieve only partial remission, or experience recurrent relapses, cytotoxic drugs such as cyclophosphamide, chlorambucil, or azathioprine may be added, which can be effective in some cases, increasing remission rates and reducing relapses. When adult cases present with nephrotic syndrome and renal biopsy reveals grade II to severe diffuse mesangial proliferation with superimposed focal segmental glomerulosclerosis, they often respond poorly to glucocorticoids, tend to have persistent proteinuria, and slowly progress to renal insufficiency. The prognosis is worse in these patients if they also exhibit glomerular adhesions, glomerular sclerosis, tubular atrophy, and interstitial fibrosis. For such cases, after an 8-week trial of standard-dose prednisone without effect, treatment should be switched to alternate-day dosing with reduced doses, adjusting the course based on disease progression while monitoring and minimizing glucocorticoid side effects. The International Study of Kidney Disease in Children (ISKDC) found that for patients with significant mesangial cell proliferation, extending glucocorticoid therapy for over one year yields more satisfactory outcomes. However, caution is still required when applying this regimen to adults. For typical mesangial proliferative glomerulonephritis with IgM-dominant deposits, the response to glucocorticoids is also poor, and progression to focal segmental glomerulosclerosis is common. In summary, patients who respond well to glucocorticoid therapy generally have a better prognosis, although proteinuria may fluctuate, with only a minority progressing to end-stage renal disease. In contrast, patients with persistent nephrotic syndrome who do not respond to glucocorticoids have a poorer prognosis, though the rate of renal failure progression varies. It remains unclear whether cytotoxic drugs can slow disease progression. Some estimates suggest that patients with superimposed focal segmental glomerulosclerosis at onset and no response to glucocorticoids often develop renal failure within 5–10 years. For severe mesangial proliferative glomerulonephritis with superimposed focal segmental glomerulosclerosis and nephrotic syndrome progressing to renal failure within three years, renal transplantation has been reported to carry a high risk of recurrent glomerulonephritis in the graft.