Mesangioproliferative glomerulonephritis

Mesangioproliferative glomerulonephritis is characterized by proliferation of mesangial cells, expansion of the mesangium, and deposition of immune complexes in the mesangium and under the endothelium.

Mesangioproliferative glomerulonephritis is a fairly common morphological type of glomerulonephritis, which meets (unlike the previous variants) all the criteria of glomerulonephritis as an immune-inflammatory disease. The main symptoms of mesangioproliferative glomerulonephritis are proteinuria, hematuria, and in some cases, nephrotic syndrome and arterial hypertension. The course of mesangioproliferative glomerulonephritis is relatively favorable. In our early observations, the 10-year survival rate (before the onset of terminal renal failure) was 81%. Currently, there is a tendency to distinguish different clinical and morphological variants depending on the class of immunoglobulins prevalent in glomerular deposits.

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Causes and pathogenesis of IgA nephropathy

The causes and pathogenesis of IgA nephropathy are under intensive study. One hypothesis suggests abnormal glycosylation of IgA, which leads to its deposition in the glomeruli and causes leukocyte activation and an inflammatory cascade.

Viral (and other infectious), food and endogenous antigens are discussed as possible etiologic factors. Among viruses, the possible role of respiratory viruses, cytomegalovirus and Epstein-Barr virus is being studied. UHF irradiation of the tonsils (possibly stimulating ARVI) causes deterioration of urine analysis, especially in those patients who have a history of macrohematuria.

There are reports on the etiologic role of mycotoxin. It is believed that mycotoxin, entering the intestine and disrupting the function of the immune system of the mucous membrane, can be the cause of IgA-H in humans.

Among food antigens, the role of gluten has been proven in some patients. In the serum of IgA-H patients, IgA-AT titers to gliadin and other food proteins are increased. The role of endogenous antigens, including heat shock proteins, is possible.

Genetic factors are also important. Associations have been described between IgA nephritis and HLA-BW35, as well as with HLA-DR4 antigen. Familial cases are possible. There are indications of a connection between IgA-H progression and ACE gene polymorphism.

Kidney damage is characterized by focal or diffuse mesangioproliferative glomerulonephritis or other types of proliferative glomerulonephritis. Currently, there is a tendency to classify other morphological types of glomerulonephritis with IgA deposition in the kidneys as IgA-H. Morphologically, IgA-H activity is assessed by the same signs as the activity of other morphological types.

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Symptoms of IgA nephropathy

Symptoms of IgA nephropathy develop at a young age, more often in men. In 50% of patients, recurrent macrohematuria is observed, which occurs with febrile respiratory diseases in the first days or even hours of illness ("synpharyngeal macrohematuria"), less often after other diseases, vaccination or heavy physical exertion. Macrohematuria is often accompanied by low-intensity dull pain in the lower back, transient hypertension, and sometimes fever. Episodes of macrohematuria can be with transient oliguric acute renal failure, presumably caused by blockage of the tubules by erythrocyte casts.

In most cases, these episodes pass without a trace, however, there are descriptions of patients in whom renal function was not fully restored after acute renal failure.

In other patients, IgA nephritis is latent, with microhematuria, often with slight proteinuria. In 15-50% of patients (usually older and/or with microhematuria), nephrotic syndrome may join in the late stages (in our observations, in 25% of patients), and in 30-35% - arterial hypertension. Among our patients with microhematuria, systemic symptoms were often noted: arthralgia, myalgia, Raynaud's syndrome, polyneuropathy, hyperuricemia.

IgA nephropathy

The main place among the variants of mesangioproliferative glomerulonephritis is occupied by glomerulonephritis with the deposition of immunoglobulin A in the glomeruli - IgA nephritis, IgA nephropathy (IgA-H), Berger's disease. It was described by J. Berger et al. in 1967 as recurrent benign hematuria. In subsequent years, with long-term observation, it was established that in 20-50% of adult patients, kidney function deteriorates over time. It is now considered a persistent or slowly progressive disease.

Currently, the scope of IgA-H is significantly expanding. A number of researchers include other types of nephritis in this group, in which IgA is detected in the glomeruli. At the same time, the terms "IgA nephritis" or more often "IgA nephropathy" are gradually being replaced by the term "Mesangioproliferative glomerulonephritis", although it is mentioned that IgA-H belongs to a large group of mesangioproliferative nephritis, which includes glomerulonephritis with C3 and IgG deposits, as well as glomerulonephritis with IgM deposits.

The problem is further complicated by the unclear relationship between IgA-H and hemorrhagic vasculitis (Schonlein-Henoch purpura), in which serum IgA levels are also elevated and IgA deposits are found in the kidneys, leading to the possibility that IgA-H is a mono-organ form of hemorrhagic vasculitis.

The frequency of IgA nephritis among other types of glomerulonephritis is approximately 30% in Asia and 10-12% in Europe and Australia. In some countries (Japan), IgA nephritis has become prevalent (25-50%) among all cases of chronic glomerulonephritis. According to our clinic, it was detected in 12.7% of 1218 morphologically confirmed cases of glomerulonephritis (8.5% of all biopsies).

Diagnosis of IgA nephropathy

In the blood serum of 35-60% of patients, the IgA content is elevated, with its polymeric forms predominating. The degree of IgA elevation does not reflect the clinical course of the disease and does not affect the prognosis. High titers of IgA-containing immune complexes are also detected in the serum, which in some cases contain antibodies against bacterial, viral and food antigens. Serum complement is usually normal.

Differential diagnostics of IgA nephropathy is carried out with urolithiasis, kidney tumors, IgA nephritis in hemorrhagic vasculitis and chronic alcoholism, Alport syndrome, and thin basement membrane disease.

Thin basement membrane disease (benign familial hematuria) is a disease with a good prognosis, occurring with microhematuria; usually inherited in an autosomal dominant manner; there are no IgA deposits in the kidneys; for final confirmation of the diagnosis, it is necessary to measure the thickness of the GBM by electron microscopy, which is 191 nm in thin membrane disease, and 326 nm in IgA-H.

The course of IgA-H is relatively favorable, especially in patients with macrohematuria. Renal failure develops after 10-15 years in 15-30% of patients, progressing slowly.

Factors that worsen the prognosis of IgA nephropathy:

• severe microhematuria;
• pronounced proteinuria;
• arterial hypertension;
• renal failure;
• severity of morphological changes (glomerular sclerosis, interstitium);
• deposition of IgA in the walls of peripheral vessels;
• male gender;
• older age at onset of the disease.

L. Frimat et al. (1997) in a prospective study identified 3 main clinical factors of poor prognosis: male gender, daily proteinuria level above 1 g and serum creatinine level above 150 mmol/l.

IgA-H often recurs in the graft, in 50% of recipients within 2 years. However, cadaveric kidney transplantation has better graft survival than other kidney diseases. Transplantation from HLA-identical siblings is not recommended.

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Treatment of mesangioproliferative glomerulonephritis and IgA nephropathy

Currently, treatment for mesangioproliferative glomerulonephritis and IgA nephropathy has not been developed. This can be partly explained by the high variability of disease outcomes (terminal renal failure develops only in some patients, and at different rates) and the difficulty of predicting the prognosis in each individual patient, even taking into account the already established clinical and morphological prognostic factors. Most studies performed to date, which concluded that proteinuria decreases or function stabilizes as a result of therapy, are based either on individual observations or on retrospective data analysis.

Elimination of foci of infection, tonsillectomy

The effectiveness of other measures aimed at preventing exacerbations of infection, namely removal of the source of infection (tonsillectomy) and long-term antibiotic therapy, is still being debated. Tonsillectomy does reduce the number of macrohematuria episodes, and sometimes also proteinuria and the level of IgA in the serum. There is evidence of a possible inhibitory effect of tonsillectomy on the progression of the renal process. In this regard, tonsillectomy can be recommended to patients with frequent exacerbations of tonsillitis.

Some authors believe that short-term antibiotic treatment of acute respiratory or gastrointestinal infection is justified, especially when the infection provokes episodes of macrohematuria.

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Glucocorticosteroids and cytostatics

There is no evidence of a significant effect of immunosuppressants (glucocorticoids or their combination with cytostatics) on the course of slowly progressive forms of the disease.

A large multicenter Italian study that assessed the efficacy of glucocorticoids (alternating regimen) in patients with a high risk of progression - proteinuria level of 1-3.5 g/day, confirmed a reduction in proteinuria and stabilization of renal function.

In our observations, cytostatic therapy was effective in 59% of patients with mesangioproliferative glomerulonephritis. In a randomized prospective study, the effectiveness of pulse therapy with cyclophosphamide was the same as with oral administration, but there were significantly fewer side effects.

Cyclophosphamide, dipyridamole, warfarin (phenylin)

This three-component method (cyclophosphamide for 6 months, the other two drugs for 3 years) reduced proteinuria and stabilized kidney function in a controlled study from Singapore. However, a repeat assessment of patients in the Singapore study after 5 years revealed no difference in the rate of progression of renal failure in treated and untreated patients.

Cyclosporine at a dose of 5 mg/kg x day) in a randomized study reduced proteinuria, serum IgA concentration and expression of interleukin-2 receptors on T cells. V. Chabova et al. (1997) treated 6 patients with IgA nephropathy with proteinuria over 3.5 g/day (mean 4.66 g/day) and creatinine level less than 200 μmol/l with cyclosporine A; proteinuria decreased after 1 month to 1.48 and after 12 months to 0.59 g/day. Complications: hypertension (4 patients), hypertrichosis (2 patients), vomiting (1 patient). In our studies, cyclosporine A caused remission in 4 of 6 patients with resistant or steroid-dependent MPGN with nephrotic syndrome.

Fish oil containing omega-3 polyunsaturated fatty acids (which inhibit the synthesis of inflammatory prostaglandins) was ineffective in patients with IgA nephritis in three controlled trials and slowed the progression of renal failure in one controlled trial in patients with moderately impaired function (creatinine <3 mg%) given 12 g/day of fish oil for 2 years.

Thus, based on the severity of the prognosis of various variants of IgA nephropathy, the following therapeutic approaches can be recommended:

• aggressive therapy is not indicated for patients with isolated hematuria (especially with episodes of synpharyngeal macrohematuria), mild proteinuria (<1 g/day) and normal renal function. ACE inhibitors (for nephroprotective purposes) and dipyridamole may be prescribed;
• Patients at risk of progression (proteinuria >1 g within 24 hours, arterial hypertension, normal or moderately reduced renal function or morphological signs of disease activity) may be prescribed:
  • ACE inhibitors: long-term use even with normal blood pressure;
  • fish oil: 12 g/day for 2 years (effectiveness still questionable);
  • corticosteroids: oral administration of prednisolone every other day, starting with 60 mg/day for 3 months with a gradual reduction in dose;
• patients with severe proteinuria (>3 g/day) or nephrotic syndrome are indicated for active therapy - glucocorticoids, cytostatics (including in the form of CFA pulse therapy).

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