Membranous glomerulonephritis (membranous nephropathy)

Membranous glomerulonephritis (membranous nephropathy) is characterized by diffuse thickening of the glomerular capillary walls associated with diffuse subepithelial deposition of immune complexes, cleavage and duplication of the GBM. There is little or no cellular proliferation. The antigen responsible for immune complex formation in primary membranous nephropathy is unknown.

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Epidemiology

The frequency of membranous nephropathy among all morphological types of nephritis is, according to various authors, 3-15%. According to P. Zucchelli and S. Pasquali (1998), among 4060 biopsies performed over 25 years, membranous nephropathy was found in 319 cases (7.8%).

Membranous glomerulonephritis (membranous nephropathy) develops at any age, more often in adults (especially at the age of 30-50 years) than in children. It occurs more often in men than in women, and is more severe. In adults, membranous nephropathy is the most common cause of nephrotic syndrome (20-40% of cases), in children with nephrotic syndrome it is observed in less than 1% of cases.

In most patients, the main symptoms of membranous glomerulonephritis (membranous nephropathy) are nephrotic syndrome, less often proteinuria without nephrotic syndrome. Microhematuria is possible in 25-40% of patients. Macrohematuria and hypertension are rarely observed at the onset of the disease, later hypertension develops in 20-50% of patients. The serum complement content is almost always normal, rarely reduced (for example, in cases etiologically associated with viral hepatitis B or systemic lupus erythematosus).

With this type of nephritis, it is often possible (in 30-35% of patients) to establish a connection with known antigens - HBV, tumor, medicinal.

In this regard, in clinical practice, it is necessary to examine patients with membranous nephropathy especially carefully in order to possibly detect, first of all, a tumor (especially of the lungs, kidneys), infection with hepatitis viruses, etc.

Another feature is the frequent association with various systemic and other diseases: systemic lupus erythematosus, autoimmune thyroiditis, Sjogren's syndrome, diabetes mellitus, psoriasis, etc.

In patients with membranous nephropathy with nephrotic syndrome, thrombotic complications develop more often than in other morphological variants of glomerulonephritis.

RC Atkins and R. Bellomo (1993), based on their observations and literature data, provide the following figures for the frequency of thrombosis in patients with membranous nephropathy: renal vein thrombosis - in 29%, pulmonary embolism - in 17%, and deep thrombosis of the extremities - in 17%.

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Causes membranous glomerulonephritis (membranous nephropathy)

Infections	Tumors	Medicines
Hepatitis B, C Malaria Tuberculosis Schistosomiasis Filariasis Syphilis Echinococcosis	Kidney, lung, and bowel cancer Lymphomas Chronic lymphocytic leukemia	D-penicillamine Gold preparations Captopril NSAIDs

The course of membranous glomerulonephritis (membranous nephropathy) is relatively favorable (especially in women), spontaneous remissions are possible. Renal failure develops in only 50% of patients. S. Hogan et al. (1995), based on a meta-analysis of numerous published reports, cite the following frequency of recurrent terminal renal failure: 14% after 5 years, 35% after 10 years, and 41% after 15 years. The following factors negatively affect the prognosis: male gender; age over 50 years; severe nephrotic syndrome; proteinuria over 10 g/day; arterial hypertension; early increase in serum creatinine (in the first 3-5 years); severe tubulointerstitial changes; absence of remissions (spontaneous or after treatment).

Membranous nephropathy recurs in the graft in approximately 10% of patients and may also develop in a de novo kidney graft.

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Treatment membranous glomerulonephritis (membranous nephropathy)

Treatment of membranous glomerulonephritis (membranous nephropathy) will be different in patients with and without nephrotic syndrome.

Patients without nephrotic syndrome with normal renal function do not require immunosuppressive therapy, since the risk of developing renal failure is minimal and there is no risk of complications associated with nephrotic syndrome. These patients should be under regular observation to promptly detect an increase in blood pressure, proteinuria, and creatinine.

With proteinuria over 1.5-2.0 g/day, ACE inhibitors are indicated, which reduce proteinuria and slow down the progression of the disease, and with elevated cholesterol levels, lipid-lowering drugs.

In patients with nephrotic syndrome and preserved renal function, therapeutic approaches are different.

It is generally accepted to provide these patients with adequate symptomatic therapy: diuretics, ACE inhibitors - to reduce proteinuria and slow down the process, if necessary - other antihypertensive, lipid-lowering drugs, anticoagulants to prevent thrombotic complications (opinions on the latter effect are mixed).

The need for the use of immunosuppressants is the most controversial issue in the treatment of membranous glomerulonephritis (membranous nephropathy).

A number of researchers believe that MN has a very favorable prognosis, therefore patients should not be subjected to dangerous therapy, except in situations where renal dysfunction, severe proteinuria (>10 g/day) or severe manifestations of NS develop, worsening the patient's condition.

Proponents of immunosuppressive therapy favor early treatment because a certain proportion of patients may develop renal failure and severe complications of nephrotic syndrome (especially thrombosis and other cardiovascular events). Late initiation of therapy, when renal failure and tubulointerstitial changes occur, is less effective; in addition, patients with renal failure have a higher risk of complications from immunosuppressive therapy. We believe that active therapy is indicated for all patients with MN and nephrotic syndrome.

Data from recent large studies indicate that 10-year renal survival of untreated patients with MN and nephrotic syndrome is 60-65%. Spontaneous (complete or partial) remissions of nephrotic syndrome develop in 38% of untreated patients, but in most cases they appear only after 2 years of nephrotic syndrome and are extremely unstable.

The main factors that predict renal prognosis to a certain extent have been established: the greatest risk of developing professional renal failure is in elderly men, patients with high and persistent proteinuria (>1 g/day), initial decrease in renal function, focal glomerulosclerosis and severe tubulointerstitial changes. At the same time, it is impossible to predict with certainty which patients will develop spontaneous remission.

Results of different methods of treatment of membranous glomerulonephritis (membranous nephropathy)

With regard to methods of active (immunosuppressive) therapy, preference is given to cytostatics (alkylating drugs) or a combination of glucocorticoids and cytostatics.

The best results were obtained in a 10-year Italian multicenter study: 6-month treatment with monthly alternation of methylprednisolone and chlorbutin (S. Ponticelli regimen) compared with symptomatic treatment increased the frequency of remissions of nephrotic syndrome by 2 times (62% and 33%, respectively) and reduced the frequency of chronic renal failure (8% and 40% after 10 years).

Except for two uncontrolled studies in small numbers of patients, there is no data to support the efficacy of azathioprine.

A possible alternative to the combination of prednisolone and chlorbutin is the treatment of membranous glomerulonephritis (membranous nephropathy) with corticosteroids or cyclosporine alone.

Corticosteroids are used less frequently as monotherapy. In 5-10% of patients, remission may develop within a short period of time, but in most cases, corticosteroids must be used in high doses for a long time to achieve it.

It is suggested to take prednisolone every other day (200 mg every 48 hours) for 6-12 months.

Intravenous pulses of methylprednisolone (1 g over 3 days - in the 1st, 3rd and 5th months) against the background of taking prednisolone every other day (0.5 mg/kg every 48 hours) is another well-tolerated regimen, although less effective than the combination of prednisolone and chlorbutin.

In uncontrolled clinical trials, cyclosporine caused complete remissions of nephrotic syndrome in 20% of cases and partial remissions in another 25% of cases, but after cyclosporine was discontinued, most patients rapidly developed relapses. In some patients, remission can be maintained for a long time with relatively low doses [3.0-3.5 mg/kg/day] and with slow withdrawal of the drug, the risk of exacerbation is significantly reduced.

Treatment of membranous glomerulonephritis (membranous nephropathy) in elderly patients

Renal prognosis in people over 65 years of age is usually worse than in younger people. However, in the observations of P. Passerini (1993) and S. Rollino (1995), the results of 6-month therapy with MP and chlorbutin in people over and under 65 years of age did not differ significantly. At the same time, side effects in the elderly were more frequent and severe, therefore, in immunosuppressive therapy, the doses of drugs should be lower in the elderly than in the young.

The treatment approaches for patients with renal failure are the same as for patients with normal renal function. However, because of the high sensitivity of these patients to the side effects of immunosuppressants, treatment should be started only if there is a real chance of success.

Methylprednisolone pulses followed by oral prednisolone in a moderate dose in some patients with renal failure contribute to a transient decrease in creatinine levels. More encouraging results were obtained with long-term (1-2 years) cyclophosphamide or 6-month treatment with methylprednisolone and chlorbutin, but to reduce toxicity, the MP dose should be reduced to 0.5 g intravenously, and chlorbutin - 0.1 mg / kg x day).

In case of contraindications to active immunosuppressive therapy or if it is ineffective, treatment with ACE inhibitors, lipid-lowering drugs, dipyridamole, and possibly heparin is indicated.

Indications for treatment of patients with membranous nephropathy with slowly progressive renal failure

Indicator	Treat	Do not treat
Creatinine	<4.5 mg%	>4.5 mg%
Ultrasound of the kidneys:
Size	Subnormal	Decreased
Increased echogenicity	Moderate	Expressed
Kidney biopsy:
Mesangial sclerosis	Moderate	Expressed
Interstitial fibrosis	Moderate	Expressed
Immune deposits	Fresh	None